Bibliography of Microarray Studies

Here you can browse the Microarray studies used to produce our predictions.

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AuthorTitleYearJournal/ProceedingsExperiment TypeDOI/URL
Baugh, L. R., Hill, A. A., Claggett, J. M., Hill-Harfe, K., Wen, J. C., Slonim, D. K., Brown, E. L. & Hunter, C. P. The homeodomain protein PAL-1 specifies a lineage-specific regulatory network in the C. elegans embryo. 2005 Development   whole animal URL  
Abstract: Maternal and zygotic activities of the homeodomain protein PAL-1 specify the identity and maintain the development of the multipotent C blastomere lineage in the C. elegans embryo. To identify PAL-1 regulatory target genes, we used microarrays to compare transcript abundance in wild-type embryos with mutant embryos lacking a C blastomere and to mutant embryos with extra C blastomeres. pal-1-dependent C-lineage expression was verified for select candidate target genes by reporter gene analysis, though many of the target genes are expressed in additional lineages as well. The set of validated target genes includes 12 transcription factors, an uncharacterized wingless ligand and five uncharacterized genes. Phenotypic analysis demonstrates that the identified PAL-1 target genes affect specification, differentiation and morphogenesis of C-lineage cells. In particular, we show that cell fate-specific genes (or tissue identity genes) and a posterior HOX gene are activated in lineage-specific fashion. Transcription of targets is initiated in four temporal phases, which together with their spatial expression patterns leads to a model of the regulatory network specified by PAL-1.
BibTeX:
@article{Baugh2005,
  author = {L. Ryan Baugh and Andrew A Hill and Julia M Claggett and Kate Hill-Harfe and Joanne C Wen and Donna K Slonim and Eugene L Brown and Craig P Hunter},
  title = {The homeodomain protein PAL-1 specifies a lineage-specific regulatory network in the C. elegans embryo.},
  journal = {Development},
  year = {2005},
  volume = {132},
  number = {8},
  pages = {1843--1854},
  url = {http://dx.doi.org/10.1242/dev.01782},
  doi = {http://dx.doi.org/10.1242/dev.01782}
}
Baugh, L. R., Hill, A. A., Slonim, D. K., Brown, E. L. & Hunter, C. P. Composition and dynamics of the Caenorhabditis elegans early embryonic transcriptome. 2003 Development   whole animal  
Abstract: Temporal profiles of transcript abundance during embryonic development were obtained by whole-genome expression analysis from precisely staged C. elegans embryos. The result is a highly resolved time course that commences with the zygote and extends into mid-gastrulation, spanning the transition from maternal to embryonic control of development and including the presumptive specification of most major cell fates. Transcripts for nearly half (8890) of the predicted open reading frames are detected and expression levels for the majority of them (>70 change over time. The transcriptome is stable up to the four-cell stage where it begins rapidly changing until the rate of change plateaus before gastrulation. At gastrulation temporal patterns of maternal degradation and embryonic expression intersect indicating a mid-blastula transition from maternal to embryonic control of development. In addition, we find that embryonic genes tend to be expressed transiently on a time scale consistent with developmental decisions being made with each cell cycle. Furthermore, overall rates of synthesis and degradation are matched such that the transcriptome maintains a steady-state frequency distribution. Finally, a versatile analytical platform based on cluster analysis and developmental classification of genes is provided.
BibTeX:
@article{Baugh2003,
  author = {L. Ryan Baugh and Andrew A Hill and Donna K Slonim and Eugene L Brown and Craig P Hunter},
  title = {Composition and dynamics of the Caenorhabditis elegans early embryonic transcriptome.},
  journal = {Development},
  year = {2003},
  volume = {130},
  number = {5},
  pages = {889--900}
}
Bishop, T., Lau, K. W., Epstein, A. C. R., Kim, S. K., Jiang, M., O'Rourke, D., Pugh, C. W., Gleadle, J. M., Taylor, M. S., Hodgkin, J. & Ratcliffe, P. J. Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans. 2004 PLoS Biol   whole animal URL  
Abstract: The von Hippel-Lindau (VHL) tumor suppressor functions as a ubiquitin ligase that mediates proteolytic inactivation of hydroxylated alpha subunits of hypoxia-inducible factor (HIF). Although studies of VHL-defective renal carcinoma cells suggest the existence of other VHL tumor suppressor pathways, dysregulation of the HIF transcriptional cascade has extensive effects that make it difficult to distinguish whether, and to what extent, observed abnormalities in these cells represent effects on pathways that are distinct from HIF. Here, we report on a genetic analysis of HIF-dependent and -independent effects of VHL inactivation by studying gene expression patterns in Caenorhabditis elegans. We show tight conservation of the HIF-1/VHL-1/EGL-9 hydroxylase pathway. However, persisting differential gene expression in hif-1 versus hif-1; vhl-1 double mutant worms clearly distinguished HIF-1-independent effects of VHL-1 inactivation. Genomic clustering, predicted functional similarities, and a common pattern of dysregulation in both vhl-1 worms and a set of mutants (dpy-18, let-268, gon-1, mig-17, and unc-6), with different defects in extracellular matrix formation, suggest that dysregulation of these genes reflects a discrete HIF-1-independent function of VHL-1 that is connected with extracellular matrix function.
BibTeX:
@article{Bishop2004,
  author = {Tammie Bishop and Kah Weng Lau and Andrew C R Epstein and Stuart K Kim and Min Jiang and Delia O'Rourke and Christopher W Pugh and Jonathan M Gleadle and Martin S Taylor and Jonathan Hodgkin and Peter J Ratcliffe},
  title = {Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans.},
  journal = {PLoS Biol},
  year = {2004},
  volume = {2},
  number = {10},
  pages = {e289},
  url = {http://dx.doi.org/10.1371/journal.pbio.0020289},
  doi = {http://dx.doi.org/10.1371/journal.pbio.0020289}
}
Blumenthal, T., Evans, D., Link, C. D., Guffanti, A., Lawson, D., Thierry-Mieg, J., Thierry-Mieg, D., Chiu, W. L., Duke, K., Kiraly, M. & Kim, S. K. A global analysis of Caenorhabditis elegans operons. 2002 Nature   whole animal URL  
Abstract: The nematode worm Caenorhabditis elegans and its relatives are unique among animals in having operons. Operons are regulated multigene transcription units, in which polycistronic pre-messenger RNA (pre-mRNA coding for multiple peptides) is processed to monocistronic mRNAs. This occurs by 3' end formation and trans-splicing using the specialized SL2 small nuclear ribonucleoprotein particle for downstream mRNAs. Previously, the correlation between downstream location in an operon and SL2 trans-splicing has been strong, but anecdotal. Although only 28 operons have been reported, the complete sequence of the C. elegans genome reveals numerous gene clusters. To determine how many of these clusters represent operons, we probed full-genome microarrays for SL2-containing mRNAs. We found significant enrichment for about 1,200 genes, including most of a group of several hundred genes represented by complementary DNAs that contain SL2 sequence. Analysis of their genomic arrangements indicates that >90% are downstream genes, falling in 790 distinct operons. Our evidence indicates that the genome contains at least 1,000 operons, 2 8 genes long, that contain about 15% of all C. elegans genes. Numerous examples of co-transcription of genes encoding functionally related proteins are evident. Inspection of the operon list should reveal previously unknown functional relationships.
BibTeX:
@article{Blumenthal2002a,
  author = {Thomas Blumenthal and Donald Evans and Christopher D Link and Alessandro Guffanti and Daniel Lawson and Jean Thierry-Mieg and Danielle Thierry-Mieg and Wei Lu Chiu and Kyle Duke and Moni Kiraly and Stuart K Kim},
  title = {A global analysis of Caenorhabditis elegans operons.},
  journal = {Nature},
  year = {2002},
  volume = {417},
  number = {6891},
  pages = {851--854},
  url = {http://dx.doi.org/10.1038/nature00831},
  doi = {http://dx.doi.org/10.1038/nature00831}
}
Chen, N., Mah, A., Blacque, O. E., Chu, J., Phgora, K., Bakhoum, M. W., Newbury, C. R. H., Khattra, J., Chan, S., Go, A., Efimenko, E., Johnsen, R., Phirke, P., Swoboda, P., Marra, M., Moerman, D. G., Leroux, M. R., Baillie, D. L. & Stein, L. D. Identification of ciliary and ciliopathy genes in Caenorhabditis elegans through comparative genomics. 2006 Genome Biol   tissue-specifc URL  
Abstract: BACKGROUND: The recent availability of genome sequences of multiple related Caenorhabditis species has made it possible to identify, using comparative genomics, similarly transcribed genes in Caenorhabditis elegans and its sister species. Taking this approach, we have identified numerous novel ciliary genes in C. elegans, some of which may be orthologs of unidentified human ciliopathy genes. RESULTS: By screening for genes possessing canonical X-box sequences in promoters of three Caenorhabditis species, namely C. elegans, C. briggsae and C. remanei, we identified 93 genes (including known X-box regulated genes) that encode putative components of ciliated neurons in C. elegans and are subject to the same regulatory control. For many of these genes, restricted anatomical expression in ciliated cells was confirmed, and control of transcription by the ciliogenic DAF-19 RFX transcription factor was demonstrated by comparative transcriptional profiling of different tissue types and of daf-19(+) and daf-19(-) animals. Finally, we demonstrate that the dye-filling defect of dyf-5(mn400) animals, which is indicative of compromised exposure of cilia to the environment, is caused by a nonsense mutation in the serine/threonine protein kinase gene M04C9.5. CONCLUSION: Our comparative genomics-based predictions may be useful for identifying genes involved in human ciliopathies, including Bardet-Biedl Syndrome (BBS), since the C. elegans orthologs of known human BBS genes contain X-box motifs and are required for normal dye filling in C. elegans ciliated neurons.
BibTeX:
@article{Chen2006,
  author = {Nansheng Chen and Allan Mah and Oliver E Blacque and Jeffrey Chu and Kiran Phgora and Mathieu W Bakhoum and C. Rebecca Hunt Newbury and Jaswinder Khattra and Susanna Chan and Anne Go and Evgeni Efimenko and Robert Johnsen and Prasad Phirke and Peter Swoboda and Marco Marra and Donald G Moerman and Michel R Leroux and David L Baillie and Lincoln D Stein},
  title = {Identification of ciliary and ciliopathy genes in Caenorhabditis elegans through comparative genomics.},
  journal = {Genome Biol},
  year = {2006},
  volume = {7},
  number = {12},
  pages = {R126},
  url = {http://dx.doi.org/10.1186/gb-2006-7-12-r126},
  doi = {http://dx.doi.org/10.1186/gb-2006-7-12-r126}
}
Chi, W. & Reinke, V. Promotion of oogenesis and embryogenesis in the C. elegans gonad by EFL-1/DPL-1 (E2F) does not require LIN-35 (pRB). 2006 Development   tissue-specific URL  
Abstract: In Caenorhabditis elegans, EFL-1 (E2F), DPL-1 (DP) and LIN-35 (pRb) act coordinately in somatic tissues to inhibit ectopic cell division, probably by repressing the expression of target genes. EFL-1, DPL-1 and LIN-35 are also present in the germline, but do not always act together. Strong loss-of-function mutations in either efl-1 or dpl-1 cause defects in oogenesis that result in sterility, while lin-35 mutants are fertile with reduced broods. Microarray-based expression profiling of dissected gonads from efl-1, dpl-1 and lin-35 mutants reveals that EFL-1 and DPL-1 promote expression of an extensively overlapping set of target genes, consistent with the expectation that these two proteins function as a heterodimer. Regulatory regions upstream of many of these target genes have a canonical E2F-binding site, suggesting that their regulation by EFL-1/DPL-1 is direct. Many EFL-1/DPL-1 responsive genes encode proteins required for oogenesis and early embryogenesis, rather than cell cycle components. By contrast, LIN-35 appears to function primarily as a repressor of gene expression in the germline, and the genes that it acts on are for the most part distinct from those regulated by EFL-1 and/or DPL-1. Thus, in vivo, C. elegans E2F directly promotes oogenesis and embryogenesis through the activation of a tissue-specific transcriptional program that does not require LIN-35.
BibTeX:
@article{Chi2006,
  author = {Woo Chi and Valerie Reinke},
  title = {Promotion of oogenesis and embryogenesis in the C. elegans gonad by EFL-1/DPL-1 (E2F) does not require LIN-35 (pRB).},
  journal = {Development},
  year = {2006},
  volume = {133},
  number = {16},
  pages = {3147--3157},
  url = {http://dx.doi.org/10.1242/dev.02490},
  doi = {http://dx.doi.org/10.1242/dev.02490}
}
Colosimo, M. E., Brown, A., Mukhopadhyay, S., Gabel, C., Lanjuin, A. E., Samuel, A. D. T. & Sengupta, P. Identification of thermosensory and olfactory neuron-specific genes via expression profiling of single neuron types. 2004 Curr Biol   tissue-specific URL  
Abstract: Most C. elegans sensory neuron types consist of a single bilateral pair of neurons, and respond to a unique set of sensory stimuli. Although genes required for the development and function of individual sensory neuron types have been identified in forward genetic screens, these approaches are unlikely to identify genes that when mutated result in subtle or pleiotropic phenotypes. Here, we describe a complementary approach to identify sensory neuron type-specific genes via microarray analysis using RNA from sorted AWB olfactory and AFD thermosensory neurons. The expression patterns of subsets of these genes were further verified in vivo. Genes identified by this analysis encode 7-transmembrane receptors, kinases, and nuclear factors including dac-1, which encodes a homolog of the highly conserved Dachshund protein. dac-1 is expressed in a subset of sensory neurons including the AFD neurons and is regulated by the TTX-1 OTX homeodomain protein. On thermal gradients, dac-1 mutants fail to suppress a cryophilic drive but continue to track isotherms at the cultivation temperature, representing the first genetic separation of these AFD-mediated behaviors. Expression profiling of single neuron types provides a rapid, powerful, and unbiased method for identifying neuron-specific genes whose functions can then be investigated in vivo.
BibTeX:
@article{Colosimo2004,
  author = {Marc E Colosimo and Adam Brown and Saikat Mukhopadhyay and Christopher Gabel and Anne E Lanjuin and Aravinthan D T Samuel and Piali Sengupta},
  title = {Identification of thermosensory and olfactory neuron-specific genes via expression profiling of single neuron types.},
  journal = {Curr Biol},
  year = {2004},
  volume = {14},
  number = {24},
  pages = {2245--2251},
  url = {http://dx.doi.org/10.1016/j.cub.2004.12.030},
  doi = {http://dx.doi.org/10.1016/j.cub.2004.12.030}
}
Consortium, G. E. Affy: Development NA   whole animal URL  
BibTeX:
@unpublished{,
  author = {Gene Expression Consortium},
  title = {Affy: Development},
  url = {http://elegans.bcgsc.ca/home/ge_consortium.html}
}
Consortium, G. E. SAGE: Tissue-specific expression NA   tissue-specific URL  
BibTeX:
@unpublished{,
  author = {Gene Expression Consortium},
  title = {SAGE: Tissue-specific expression},
  url = {http://elegans.bcgsc.ca/home/ge_consortium.html}
}
Consortium, G. E. SAGE: Development NA   whole animal URL  
BibTeX:
@unpublished{,
  author = {Gene Expression Consortium},
  title = {SAGE: Development},
  url = {http://elegans.bcgsc.ca/home/ge_consortium.html}
}
Consortium, G. E. Nmbl: Development NA   whole animal URL  
BibTeX:
@unpublished{,
  author = {Gene Expression Consortium},
  title = {Nmbl: Development},
  url = {http://elegans.bcgsc.ca/home/ge_consortium.html}
}
Custodia, N., Won, S. J., Novillo, A., Wieland, M., Li, C. & Callard, I. P. Caenorhabditis elegans as an environmental monitor using DNA microarray analysis. 2001 Ann N Y Acad Sci   whole animal  
Abstract: In order to assist in the identification of possible endocrine disrupting chemicals (EDC) in groundwater, we are developing Caenorhabolitis elegans as a high throughput bioassay system in which responses to EDC may be detected by gene expression using DNA microarray analysis. As a first step we examined gene expression patterns and vitellogenin responses of this organism to vertebrate steroids, in liquid culture. Western blotting showed the expected number and size of vitellogenin translation products after estrogen exposure. At 10(-9) M, vitellogenin decreased, but at 10(-7) and 10(-5), vitellogenin was increased. Testosterone (10(-5) M) increased the synthesis of vitellogenin, but progesterone-treated cultures (10(-5) M) had less vitellogenin. Using DNA microarray analysis, we examined the pattern of gene expression after progesterone (10(-5), 10(-7), and 10(-9) M), estrogen (10(-5) M), and testosterone (10(-9) M) exposure, with special attention to the traditional biomarker genes used in environmental studies [vitellogenin, cytochrome P450 (CYP), glutathione s-transferase (GST), metallothionein (MT), and heat shock proteins (HSP)]. GST and P450 genes were affected by estrogen (10(-5) M) and progesterone (10(-5) and 10(-7) M) treatments. For vitellogenin genes, estrogen treatment (10(-5) M) caused overexpression of the vit-2 and vit-6 genes (2.68 and 3.25 times, respectively). After progesterone treatment (10(-7) M), the vit-5 and vit-6 were down-regulated and vit-1 up-regulated (3.59-fold). Concentrations of testosterone and progesterone at 10(-9) M did not influence the expression of the vit, CYP, or GST genes. Although the analysis is incomplete, and low doses and combinations of EDC need to be tested, these preliminary results indicate C. elegans may be a useful laboratory and field model for screening EDC.
BibTeX:
@article{Custodia2001,
  author = {N. Custodia and S. J. Won and A. Novillo and M. Wieland and C. Li and I. P. Callard},
  title = {Caenorhabditis elegans as an environmental monitor using DNA microarray analysis.},
  journal = {Ann N Y Acad Sci},
  year = {2001},
  volume = {948},
  pages = {32--42}
}
Dinkova, T. D., Keiper, B. D., Korneeva, N. L., Aamodt, E. J. & Rhoads, R. E. Translation of a small subset of Caenorhabditis elegans mRNAs is dependent on a specific eukaryotic translation initiation factor 4E isoform. 2005 Mol Cell Biol   whole animal URL  
Abstract: The mRNA cap-binding protein eukaryotic translation initiation factor 4E (eIF4E) participates in protein synthesis initiation, translational repression of specific mRNAs, and nucleocytoplasmic shuttling. Multiple isoforms of eIF4E are expressed in a variety of organisms, but their specific roles are poorly understood. We investigated one Caenorhabditis elegans isoform, IFE-4, which has homologues in plants and mammals. IFE-4::green fluorescent protein (GFP) was expressed in pharyngeal and tail neurons, body wall muscle, spermatheca, and vulva. Knockout of ife-4 by RNA interference (RNAi) or a null mutation produced a pleiotropic phenotype that included egg-laying defects. Sedimentation analysis demonstrated that IFE-4, but not IFE-1, was present in 48S initiation complexes, indicating that it participates in protein synthesis initiation. mRNAs affected by ife-4 knockout were determined by DNA microarray analysis of polysomal distribution. Polysome shifts, in the absence of total mRNA changes, were observed for only 33 of the 18,967 C. elegans mRNAs tested, of which a disproportionate number were related to egg laying and were expressed in neurons and/or muscle. Translational regulation was confirmed by reduced levels of DAF-12, EGL-15, and KIN-29. The functions of these proteins can explain some phenotypes observed in ife-4 knockout mutants. These results indicate that translation of a limited subset of mRNAs is dependent on a specific isoform of eIF4E.
BibTeX:
@article{Dinkova2005,
  author = {Tzvetanka D Dinkova and Brett D Keiper and Nadejda L Korneeva and Eric J Aamodt and Robert E Rhoads},
  title = {Translation of a small subset of Caenorhabditis elegans mRNAs is dependent on a specific eukaryotic translation initiation factor 4E isoform.},
  journal = {Mol Cell Biol},
  year = {2005},
  volume = {25},
  number = {1},
  pages = {100--113},
  url = {http://dx.doi.org/10.1128/MCB.25.1.100-113.2005},
  doi = {http://dx.doi.org/10.1128/MCB.25.1.100-113.2005}
}
Dybbs, M., Ngai, J. & Kaplan, J. M. Using microarrays to facilitate positional cloning: identification of tomosyn as an inhibitor of neurosecretion. 2005 PLoS Genet   whole animal URL  
Abstract: Forward genetic screens have been used as a powerful strategy to dissect complex biological pathways in many model systems. A significant limitation of this approach has been the time-consuming and costly process of positional cloning and molecular characterization of the mutations isolated in these screens. Here, the authors describe a strategy using microarray hybridizations to facilitate positional cloning. This method relies on the fact that premature stop codons (i.e., nonsense mutations) constitute a frequent class of mutations isolated in screens and that nonsense mutant messenger RNAs are efficiently degraded by the conserved nonsense-mediated decay pathway. They validate this strategy by identifying two previously uncharacterized mutations: (1) tom-1, a mutation found in a forward genetic screen for enhanced acetylcholine secretion in Caenorhabditis elegans, and (2) an apparently spontaneous mutation in the hif-1 transcription factor gene. They further demonstrate the broad applicability of this strategy using other known mutants in C. elegans,Arabidopsis, and mouse. Characterization of tom-1 mutants suggests that TOM-1, the C. elegans ortholog of mammalian tomosyn, functions as an endogenous inhibitor of neurotransmitter secretion. These results also suggest that microarray hybridizations have the potential to significantly reduce the time and effort required for positional cloning.
BibTeX:
@article{Dybbs2005,
  author = {Michael Dybbs and John Ngai and Joshua M Kaplan},
  title = {Using microarrays to facilitate positional cloning: identification of tomosyn as an inhibitor of neurosecretion.},
  journal = {PLoS Genet},
  year = {2005},
  volume = {1},
  number = {1},
  pages = {6--16},
  url = {http://dx.doi.org/10.1371/journal.pgen.0010002},
  doi = {http://dx.doi.org/10.1371/journal.pgen.0010002}
}
Fox, R. M., Stetina, S. E. V., Barlow, S. J., Shaffer, C., Olszewski, K. L., Moore, J. H., Dupuy, D., Vidal, M. & Miller, D. M. A gene expression fingerprint of C. elegans embryonic motor neurons. 2005 BMC Genomics   tissue-specific URL  
Abstract: BACKGROUND: Differential gene expression specifies the highly diverse cell types that constitute the nervous system. With its sequenced genome and simple, well-defined neuroanatomy, the nematode C. elegans is a useful model system in which to correlate gene expression with neuron identity. The UNC-4 transcription factor is expressed in thirteen embryonic motor neurons where it specifies axonal morphology and synaptic function. These cells can be marked with an unc-4::GFP reporter transgene. Here we describe a powerful strategy, Micro-Array Profiling of C. elegans cells (MAPCeL), and confirm that this approach provides a comprehensive gene expression profile of unc-4::GFP motor neurons in vivo. RESULTS: Fluorescence Activated Cell Sorting (FACS) was used to isolate unc-4::GFP neurons from primary cultures of C. elegans embryonic cells. Microarray experiments detected 6,217 unique transcripts of which approximately 1,000 are enriched in unc-4::GFP neurons relative to the average nematode embryonic cell. The reliability of these data was validated by the detection of known cell-specific transcripts and by expression in UNC-4 motor neurons of GFP reporters derived from the enriched data set. In addition to genes involved in neurotransmitter packaging and release, the microarray data include transcripts for receptors to a remarkably wide variety of signaling molecules. The added presence of a robust array of G-protein pathway components is indicative of complex and highly integrated mechanisms for modulating motor neuron activity. Over half of the enriched genes (537) have human homologs, a finding that could reflect substantial overlap with the gene expression repertoire of mammalian motor neurons. CONCLUSION: We have described a microarray-based method, MAPCeL, for profiling gene expression in specific C. elegans motor neurons and provide evidence that this approach can reveal candidate genes for key roles in the differentiation and function of these cells. These methods can now be applied to generate a gene expression map of the C. elegans nervous system.
BibTeX:
@article{Fox2005,
  author = {Rebecca M Fox and Stephen E Von Stetina and Susan J Barlow and Christian Shaffer and Kellen L Olszewski and Jason H Moore and Denis Dupuy and Marc Vidal and David M Miller},
  title = {A gene expression fingerprint of C. elegans embryonic motor neurons.},
  journal = {BMC Genomics},
  year = {2005},
  volume = {6},
  number = {1},
  pages = {42},
  url = {http://dx.doi.org/10.1186/1471-2164-6-42},
  doi = {http://dx.doi.org/10.1186/1471-2164-6-42}
}
Fox, R. M., Watson, J. D., Stetina, S. E. V., McDermott, J., Brodigan, T. M., Fukushige, T., Krause, M. & Miller, D. M. The embryonic muscle transcriptome of Caenorhabditis elegans. 2007 Genome Biol   tissue-specific URL  
Abstract: BACKGROUND: The force generating mechanism of muscle is evolutionarily ancient; the fundamental structural and functional components of the sarcomere are common to motile animals throughout phylogeny. Recent evidence suggests that the transcription factors that regulate muscle development are also conserved. Thus, a comprehensive description of muscle gene expression in a simple model organism should define a basic muscle transcriptome that is also found in animals with more complex body plans. To this end, we applied microarray profiling of Caenorhabtidis elegans cells (MAPCeL) to muscle cell populations extracted from developing C. elegans embryos. RESULTS: We used fluorescence-activated cell sorting to isolate myo-3::green fluorescent protein (GFP) positive muscle cells, and their cultured derivatives, from dissociated early C. elegans embryos. Microarray analysis identified 7,070 expressed genes, 1,312 of which are enriched in the myo-3::GFP positive cell population relative to the average embryonic cell. The muscle enriched gene set was validated by comparisons with known muscle markers, independently derived expression data, and GFP reporters in transgenic strains. These results confirm the utility of MAPCeL for cell type specific expression profiling and reveal that 60% of these transcripts have human homologs. CONCLUSION: This study provides a comprehensive description of gene expression in developing C. elegans embryonic muscle cells. The finding that more than half of these muscle enriched transcripts encode proteins with human homologs suggests that mutant analysis of these genes in C. elegans could reveal evolutionarily conserved models of muscle gene function, with ready application to human muscle pathologies.
BibTeX:
@article{Fox2007,
  author = {Rebecca M Fox and Joseph D Watson and Stephen E Von Stetina and Joan McDermott and Thomas M Brodigan and Tetsunari Fukushige and Michael Krause and David M Miller},
  title = {The embryonic muscle transcriptome of Caenorhabditis elegans.},
  journal = {Genome Biol},
  year = {2007},
  volume = {8},
  number = {9},
  pages = {R188},
  url = {http://dx.doi.org/10.1186/gb-2007-8-9-r188},
  doi = {http://dx.doi.org/10.1186/gb-2007-8-9-r188}
}
Gaudet, J. & Mango, S. E. Regulation of organogenesis by the Caenorhabditis elegans FoxA protein PHA-4. 2002 Science   tissue-specific URL  
Abstract: The pha-4 locus encodes a forkhead box A (FoxA/HNF3) transcription factor homolog that specifies organ identity for Caenorhabditis elegans pharyngeal cells. We used microarrays to identify pharyngeal genes and analyzed those genes to determine which were direct PHA-4 targets. Our data suggest that PHA-4 directly activates most or all pharyngeal genes. Furthermore, the relative affinity of PHA-4 for different TRTTKRY (R = A/G, K = T/G, Y = T/C) elements modulates the onset of gene expression, providing a mechanism to activate pharyngeal genes at different developmental stages. We suggest that direct transcriptional regulation of entire gene networks may be a common feature of organ identity genes.
BibTeX:
@article{Gaudet2002,
  author = {J. Gaudet and S. E. Mango},
  title = {Regulation of organogenesis by the Caenorhabditis elegans FoxA protein PHA-4.},
  journal = {Science},
  year = {2002},
  volume = {295},
  number = {5556},
  pages = {821--825},
  url = {http://dx.doi.org/10.1126/science.1065175},
  doi = {http://dx.doi.org/10.1126/science.1065175}
}
Gaudet, J., Muttumu, S., Horner, M. & Mango, S. E. Whole-genome analysis of temporal gene expression during foregut development. 2004 PLoS Biol   tissue-specific URL  
Abstract: We have investigated the cis-regulatory network that mediates temporal gene expression during organogenesis. Previous studies demonstrated that the organ selector gene pha-4/FoxA is critical to establish the onset of transcription of Caenorhabditis elegans foregut (pharynx) genes. Here, we discover additional cis-regulatory elements that function in combination with PHA-4. We use a computational approach to identify candidate cis-regulatory sites for genes activated either early or late during pharyngeal development. Analysis of natural or synthetic promoters reveals that six of these sites function in vivo. The newly discovered temporal elements, together with predicted PHA-4 sites, account for the onset of expression of roughly half of the pharyngeal genes examined. Moreover, combinations of temporal elements and PHA-4 sites can be used in genome-wide searches to predict pharyngeal genes, with more than 85% accuracy for their onset of expression. These findings suggest a regulatory code for temporal gene expression during foregut development and provide a means to predict gene expression patterns based solely on genomic sequence.
BibTeX:
@article{Gaudet2004,
  author = {Jeb Gaudet and Srikanth Muttumu and Michael Horner and Susan E Mango},
  title = {Whole-genome analysis of temporal gene expression during foregut development.},
  journal = {PLoS Biol},
  year = {2004},
  volume = {2},
  number = {11},
  pages = {e352},
  url = {http://dx.doi.org/10.1371/journal.pbio.0020352},
  doi = {http://dx.doi.org/10.1371/journal.pbio.0020352}
}
Golden, T. R. & Melov, S. Microarray analysis of gene expression with age in individual nematodes. 2004 Aging Cell   whole animal URL  
Abstract: We compare the aging of wild-type and long-lived C. elegans by gene expression profiling of individual nematodes. Using a custom cDNA array, we have characterized the gene expression of 4-5 individuals at 4 distinct ages throughout the adult lifespan of wild-type N2 nematodes, and at the same ages for individuals of the long-lived strain daf-2(e1370). Using statistical tools developed for microarray data analysis, we identify genes that differentiate aging N2 from aging daf-2, as well as classes of genes that change with age in a similar way in both genotypes. Our novel approach of studying individual nematodes provides practical advantages, since it obviates the use of mutants or drugs to block reproduction, as well as the use of stressful mass-culturing procedures, that have been required for previous microarray studies of C. elegans. In addition, this approach has the potential to uncover the molecular variability between individuals of a population, variation that is missed when studying pools of thousands of individuals.
BibTeX:
@article{Golden2004,
  author = {Tamara R Golden and Simon Melov},
  title = {Microarray analysis of gene expression with age in individual nematodes.},
  journal = {Aging Cell},
  year = {2004},
  volume = {3},
  number = {3},
  pages = {111--124},
  url = {http://dx.doi.org/10.1111/j.1474-9728.2004.00095.x},
  doi = {http://dx.doi.org/10.1111/j.1474-9728.2004.00095.x}
}
GuhaThakurta, D., Palomar, L., Stormo, G. D., Tedesco, P., Johnson, T. E., Walker, D. W., Lithgow, G., Kim, S. & Link, C. D. Identification of a novel cis-regulatory element involved in the heat shock response in Caenorhabditis elegans using microarray gene expression and computational methods. 2002 Genome Res   whole animal URL  
Abstract: We report here the identification of a previously unknown transcription regulatory element for heat shock (HS) genes in Caenorhabditis elegans. We monitored the expression pattern of 11,917 genes from C. elegans to determine the genes that were up-regulated on HS. Twenty eight genes were observed to be consistently up-regulated in several different repetitions of the experiments. We analyzed the upstream regions of these genes using computational DNA pattern recognition methods. Two potential cis-regulatory motifs were identified in this way. One of these motifs (TTCTAGAA) was the DNA binding motif for the heat shock factor (HSF), whereas the other (GGGTGTC) was previously unreported in the literature. We determined the significance of these motifs for the HS genes using different statistical tests and parameters. Comparative sequence analysis of orthologous HS genes from C. elegans and Caenorhabditis briggsae indicated that the identified DNA regulatory motifs are conserved across related species. The role of the identified DNA sites in regulation of HS genes was tested by in vitro mutagenesis of a green fluorescent protein (GFP) reporter transgene driven by the C. elegans hsp-16-2 promoter. DNA sites corresponding to both motifs are shown to play a significant role in up-regulation of the hsp-16-2 gene on HS. This is one of the rare instances in which a novel regulatory element, identified using computational methods, is shown to be biologically active. The contributions of individual sites toward induction of transcription on HS are nonadditive, which indicates interaction and cross-talk between the sites, possibly through the transcription factors (TFs) binding to these sites.
BibTeX:
@article{GuhaThakurta2002,
  author = {Debraj GuhaThakurta and Lisanne Palomar and Gary D Stormo and Pat Tedesco and Thomas E Johnson and David W Walker and Gordon Lithgow and Stuart Kim and Christopher D Link},
  title = {Identification of a novel cis-regulatory element involved in the heat shock response in Caenorhabditis elegans using microarray gene expression and computational methods.},
  journal = {Genome Res},
  year = {2002},
  volume = {12},
  number = {5},
  pages = {701--712},
  url = {http://dx.doi.org/10.1101/gr.228902},
  doi = {http://dx.doi.org/10.1101/gr.228902}
}
Hill, A. A., Hunter, C. P., Tsung, B. T., Tucker-Kellogg, G. & Brown, E. L. Genomic analysis of gene expression in C. elegans. 2000 Science   whole animal  
Abstract: Until now, genome-wide transcriptional profiling has been limited to single-cell organisms. The nematode Caenorhabditis elegans is a well-characterized metazoan in which the expression of all genes can be monitored by oligonucleotide arrays. We used such arrays to quantitate the expression of C. elegans genes throughout the development of this organism. The results provide an estimate of the number of expressed genes in the nematode, reveal relations between gene function and gene expression that can guide analysis of uncharacterized worm genes, and demonstrate a shift in expression from evolutionarily conserved genes to worm-specific genes over the course of development.
BibTeX:
@article{Hill2000,
  author = {A. A. Hill and C. P. Hunter and B. T. Tsung and G. Tucker-Kellogg and E. L. Brown},
  title = {Genomic analysis of gene expression in C. elegans.},
  journal = {Science},
  year = {2000},
  volume = {290},
  number = {5492},
  pages = {809--812}
}
Jiang, M., Ryu, J., Kiraly, M., Duke, K., Reinke, V. & Kim, S. K. Genome-wide analysis of developmental and sex-regulated gene expression profiles in Caenorhabditis elegans. 2001 Proc Natl Acad Sci U S A   whole animal URL  
Abstract: We have constructed DNA microarrays containing 17,871 genes, representing about 94% of the 18,967 genes currently annotated in the Caenorhabditis elegans genome. These DNA microarrays can be used as a tool to define a nearly complete molecular profile of gene expression levels associated with different developmental stages, growth conditions, or worm strains. Here, we used these full-genome DNA microarrays to show the relative levels of gene expression for nearly every gene during development, from eggs through adulthood. These expression data can help reveal when a gene may act during development. We also compared gene expression in males to that of hermaphrodites and found a total of 2,171 sex-regulated genes (P < 0.05). The sex-regulated genes provide a global view of the differences between the sexes at a molecular level and identify many genes likely to be involved in sex-specific differentiation and behavior.
BibTeX:
@article{Jiang2001,
  author = {M. Jiang and J. Ryu and M. Kiraly and K. Duke and V. Reinke and S. K. Kim},
  title = {Genome-wide analysis of developmental and sex-regulated gene expression profiles in Caenorhabditis elegans.},
  journal = {Proc Natl Acad Sci U S A},
  year = {2001},
  volume = {98},
  number = {1},
  pages = {218--223},
  url = {http://dx.doi.org/10.1073/pnas.011520898},
  doi = {http://dx.doi.org/10.1073/pnas.011520898}
}
Kirienko, N. V. & Fay, D. S. Transcriptome profiling of the C. elegans Rb ortholog reveals diverse developmental roles. 2007 Dev Biol   whole animal URL  
Abstract: LIN-35 is the single C. elegans ortholog of the mammalian pocket protein family members, pRb, p107, and p130. To gain insight into the roles of pocket proteins during development, a microarray analysis was performed with lin-35 mutants. Stage-specific regulation patterns were revealed, indicating that LIN-35 plays diverse roles at distinct developmental stages. LIN-35 was found to repress the expression of many genes involved in cell proliferation in larvae, an activity that is carried out in conjunction with E2F. In addition, LIN-35 was found to regulate neuronal genes during embryogenesis and targets of the intestinal-specific GATA transcription factor, ELT-2, at multiple developmental stages. Additional findings suggest that LIN-35 functions in cell cycle regulation in embryos in a manner that is independent of E2F. A comparison of LIN-35-regulated genes with known fly and mammalian pocket protein targets revealed a high degree of overlap, indicating strong conservation of pocket protein functions in diverse phyla. Based on microarray results and our refinement of the C. elegans E2F consensus sequence, we were able to generate a comprehensive list of putative E2F-regulated genes in C. elegans. These results implicate a large number of genes previously unconnected to cell cycle control as having potential roles in this process.
BibTeX:
@article{Kirienko2007,
  author = {Natalia V Kirienko and David S Fay},
  title = {Transcriptome profiling of the C. elegans Rb ortholog reveals diverse developmental roles.},
  journal = {Dev Biol},
  year = {2007},
  volume = {305},
  number = {2},
  pages = {674--684},
  url = {http://dx.doi.org/10.1016/j.ydbio.2007.02.021},
  doi = {http://dx.doi.org/10.1016/j.ydbio.2007.02.021}
}
Kniazeva, M., Crawford, Q. T., Seiber, M., Wang, C. & Han, M. Monomethyl branched-chain fatty acids play an essential role in Caenorhabditis elegans development. 2004 PLoS Biol   whole animal URL  
Abstract: Monomethyl branched-chain fatty acids (mmBCFAs) are commonly found in many organisms from bacteria to mammals. In humans, they have been detected in skin, brain, blood, and cancer cells. Despite a broad distribution, mmBCFAs remain exotic in eukaryotes, where their origin and physiological roles are not understood. Here we report our study of the function and regulation of mmBCFAs in Caenorhabditis elegans, combining genetics, gas chromatography, and DNA microarray analysis. We show that C. elegans synthesizes mmBCFAs de novo and utilizes the long-chain fatty acid elongation enzymes ELO-5 and ELO-6 to produce two mmBCFAs, C15ISO and C17ISO. These mmBCFAs are essential for C. elegans growth and development, as suppression of their biosynthesis results in a growth arrest at the first larval stage. The arrest is reversible and can be overcome by feeding the arrested animals with mmBCFA supplements. We show not only that the levels of C15ISO and C17ISO affect the expression of several genes, but also that the activities of some of these genes affect biosynthesis of mmBCFAs, suggesting a potential feedback regulation. One of the genes, lpd-1, encodes a homolog of a mammalian sterol regulatory element-binding protein (SREBP 1c). We present results suggesting that elo-5 and elo-6 may be transcriptional targets of LPD-1. This study exposes unexpected and crucial physiological functions of C15ISO and C17ISO in C. elegans and suggests a potentially important role for mmBCFAs in other eukaryotes.
BibTeX:
@article{Kniazeva2004,
  author = {Marina Kniazeva and Quinn T Crawford and Matt Seiber and Cun-Yu Wang and Min Han},
  title = {Monomethyl branched-chain fatty acids play an essential role in Caenorhabditis elegans development.},
  journal = {PLoS Biol},
  year = {2004},
  volume = {2},
  number = {9},
  pages = {E257},
  url = {http://dx.doi.org/10.1371/journal.pbio.0020257},
  doi = {http://dx.doi.org/10.1371/journal.pbio.0020257}
}
Kwon, J. Y., Hong, M., Choi, M. S., Kang, S., Duke, K., Kim, S., Lee, S. & Lee, J. Ethanol-response genes and their regulation analyzed by a microarray and comparative genomic approach in the nematode Caenorhabditis elegans. 2004 Genomics   whole animal URL  
Abstract: The nematode shows responses to acute ethanol exposure that are similar to those observed in humans, mice, and Drosophila, namely hyperactivity followed by uncoordination and sedation. We used in this report the nematode Caenorhabditis elegans as a model system to identify and characterize the genes that are affected by ethanol exposure and to link those genes functionally into an ethanol-induced gene network. By analyzing the expression profiles of all C. elegans ORFs using microarrays, we identified 230 genes affected by ethanol. While the ethanol response of some of the identified genes was significant at early time points, that of the majority was at late time points, indicating that the genes in the latter case might represent the physiological consequence of the ethanol exposure. We further characterized the early response genes that may represent those involved directly in the ethanol response. These genes included many heat shock protein genes, indicating that high concentration of ethanol acts as a strong stress to the animal. Interestingly, we identified two non-heat-shock protein genes that were specifically responsive to ethanol. glr-2 was the only glutamate receptor gene to be induced by ethanol. T28C12.4, which encodes a protein with limited homology to human neuroligin, was also specific to ethanol stress. Finally, by analyzing the promoter regions of the early response genes, we identified a regulatory element, TCTGCGTCTCT, that was necessary for the expression of subsets of ethanol response genes.
BibTeX:
@article{Kwon2004,
  author = {Jae Young Kwon and Mingi Hong and Min Sung Choi and Sujin Kang and Kyle Duke and Stuart Kim and Sunho Lee and Junho Lee},
  title = {Ethanol-response genes and their regulation analyzed by a microarray and comparative genomic approach in the nematode Caenorhabditis elegans.},
  journal = {Genomics},
  year = {2004},
  volume = {83},
  number = {4},
  pages = {600--614},
  url = {http://dx.doi.org/10.1016/j.ygeno.2003.10.008},
  doi = {http://dx.doi.org/10.1016/j.ygeno.2003.10.008}
}
Leacock, S. W. & Reinke, V. Expression profiling of MAP kinase-mediated meiotic progression in Caenorhabditis elegans. 2006 PLoS Genet   tissue-specific URL  
Abstract: The LET-60 (Ras)/LIN-45 (Raf)/MPK-1 (MAP kinase) signaling pathway plays a key role in the development of multiple tissues in Caenorhabditis elegans. For the most part, the identities of the downstream genes that act as the ultimate effectors of MPK-1 signaling have remained elusive. A unique allele of mpk-1, ga111, displays a reversible, temperature-sensitive, tissue-specific defect in progression through meiotic prophase I. We performed gene expression profiling on mpk-1(ga111) animals to identify candidate downstream effectors of MPK-1 signaling in the germ line. This analysis delineated a cohort of genes whose expression requires MPK-1 signaling in germ cells in the pachytene stage of meiosis I. RNA in situ hybridization analysis shows that these genes are expressed in the germ line in an MPK-1-dependent manner and have a spatial expression pattern consistent with the location of activated MPK-1. We found that one MPK-1 signaling-responsive gene encoding a C2H2 zinc finger protein plays a role in meiotic chromosome segregation downstream of MPK-1. Additionally, discovery of genes responsive to MPK-1 signaling permitted us to order MPK-1 signaling relative to several events occurring in pachytene, including EFL-1/DPL-1 gene regulation and X chromosome reactivation. This study highlights the utility of applying global gene expression methods to investigate genes downstream of commonly used signaling pathways in vivo.
BibTeX:
@article{Leacock2006,
  author = {Stefanie W Leacock and Valerie Reinke},
  title = {Expression profiling of MAP kinase-mediated meiotic progression in Caenorhabditis elegans.},
  journal = {PLoS Genet},
  year = {2006},
  volume = {2},
  number = {11},
  pages = {e174},
  url = {http://dx.doi.org/10.1371/journal.pgen.0020174},
  doi = {http://dx.doi.org/10.1371/journal.pgen.0020174}
}
Lee, R. C., Hammell, C. M. & Ambros, V. Interacting endogenous and exogenous RNAi pathways in Caenorhabditis elegans. 2006 RNA   whole animal URL  
Abstract: C. elegans contains numerous small RNAs of ~21-24 nt in length. The microRNAs (miRNAs) are small noncoding RNAs produced by DCR-1- and ALG-dependent processing of self-complementary hairpin transcripts. Endogenous small interfering RNAs (endo-siRNAs), associated with ongoing silencing of protein-coding genes in normal worms, are produced by mechanisms that involve DCR-1 but, unlike miRNAs, also involve RDE-2, RDE-3, RDE-4, RRF-1, and RRF-3. The tiny noncoding (tncRNAs) are similar to endo-siRNAs in their biogenesis except that they are derived from noncoding sequences. These endo-siRNA- and tncRNA-based endogenous RNAi pathways involve some components, including DCR-1 and RDE-4, that are shared with exogenous RNAi, and some components, including RRF-3 and ERI-1, that are specific to endogenous RNAi. rrf-3 and eri-1 mutants are enhanced for some silencing processes and defective for others, suggesting cross-regulatory interactions between RNAi pathways in C. elegans. Microarray expression profiling of RNAi-defective mutant worms further suggests diverse endogenous RNAi pathways for silencing different sets of genes.
BibTeX:
@article{Lee2006,
  author = {Rosalind C Lee and Christopher M Hammell and Victor Ambros},
  title = {Interacting endogenous and exogenous RNAi pathways in Caenorhabditis elegans.},
  journal = {RNA},
  year = {2006},
  volume = {12},
  number = {4},
  pages = {589--597},
  url = {http://dx.doi.org/10.1261/rna.2231506},
  doi = {http://dx.doi.org/10.1261/rna.2231506}
}
Li, Y., Alvarez, O. A., Gutteling, E. W., Tijsterman, M., Fu, J., Riksen, J. A. G., Hazendonk, E., Prins, P., Plasterk, R. H. A., Jansen, R. C., Breitling, R. & Kammenga, J. E. Mapping determinants of gene expression plasticity by genetical genomics in C. elegans. 2006 PLoS Genet   whole animal URL  
Abstract: Recent genetical genomics studies have provided intimate views on gene regulatory networks. Gene expression variations between genetically different individuals have been mapped to the causal regulatory regions, termed expression quantitative trait loci. Whether the environment-induced plastic response of gene expression also shows heritable difference has not yet been studied. Here we show that differential expression induced by temperatures of 16 degrees C and 24 degrees C has a strong genetic component in Caenorhabditis elegans recombinant inbred strains derived from a cross between strains CB4856 (Hawaii) and N2 (Bristol). No less than 59% of 308 trans-acting genes showed a significant eQTL-by-environment interaction, here termed plasticity quantitative trait loci. In contrast, only 8% of an estimated 188 cis-acting genes showed such interaction. This indicates that heritable differences in plastic responses of gene expression are largely regulated in trans. This regulation is spread over many different regulators. However, for one group of trans-genes we found prominent evidence for a common master regulator: a transband of 66 coregulated genes appeared at 24 degrees C. Our results suggest widespread genetic variation of differential expression responses to environmental impacts and demonstrate the potential of genetical genomics for mapping the molecular determinants of phenotypic plasticity.
BibTeX:
@article{Li2006,
  author = {Yang Li and Olga Alda Alvarez and Evert W Gutteling and Marcel Tijsterman and Jingyuan Fu and Joost A G Riksen and Esther Hazendonk and Pjotr Prins and Ronald H A Plasterk and Ritsert C Jansen and Rainer Breitling and Jan E Kammenga},
  title = {Mapping determinants of gene expression plasticity by genetical genomics in C. elegans.},
  journal = {PLoS Genet},
  year = {2006},
  volume = {2},
  number = {12},
  pages = {e222},
  url = {http://dx.doi.org/10.1371/journal.pgen.0020222},
  doi = {http://dx.doi.org/10.1371/journal.pgen.0020222}
}
Link, C. D., Taft, A., Kapulkin, V., Duke, K., Kim, S., Fei, Q., Wood, D. E. & Sahagan, B. G. Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer's disease model. 2003 Neurobiol Aging   whole animal  
Abstract: We have engineered transgenic Caenorhabditis elegans animals to inducibly express the human beta amyloid peptide (Abeta). Gene expression changes resulting from Abeta induction have been monitored by cDNA hybridization to glass slide microarrays containing probes for almost all known or predicted C. elegans genes. Using statistical criteria, we have identified 67 up-regulated and 240 down-regulated genes. Subsets of these regulated genes have been tested and confirmed by quantitative RT-PCR. To investigate whether genes identified in this model system also show gene expression changes in Alzheimer's disease (AD) brain, we have also used quantitative RT-PCR to examine in post-mortem AD brain tissue transcript levels of alphaB-crystallin (CRYAB) and tumor necrosis factor-induced protein 1 (TNFAIP1), human homologs of genes found to be robustly induced in the transgenic C. elegans model. Both CRYAB and TNFAIP1 show increased transcript levels in AD brains, supporting the validity of this approach.
BibTeX:
@article{Link2003,
  author = {Christopher D Link and Andrew Taft and Vadim Kapulkin and Kyle Duke and Stuart Kim and Qing Fei and Douglas E Wood and Barbara G Sahagan},
  title = {Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer's disease model.},
  journal = {Neurobiol Aging},
  year = {2003},
  volume = {24},
  number = {3},
  pages = {397--413}
}
Liu, T., Zimmerman, K. K. & Patterson, G. I. Regulation of signaling genes by TGFbeta during entry into dauer diapause in C. elegans. 2004 BMC Dev Biol   whole animal URL  
Abstract: BACKGROUND: When resources are scant, C. elegans larvae arrest as long-lived dauers under the control of insulin/IGF- and TGFbeta-related signaling pathways. However, critical questions remain regarding the regulation of this developmental event. How do three dozen insulin-like proteins regulate one tyrosine kinase receptor to control complex events in dauer, metabolism and aging? How are signals from the TGFbeta and insulin/IGF pathways integrated? What gene expression programs do these pathways regulate, and how do they control complex downstream events? RESULTS: We have identified genes that show different levels of expression in a comparison of wild-type L2 or L3 larvae (non-dauer) to TGFbeta mutants at similar developmental stages undergoing dauer formation. Many insulin/IGF pathway and other known dauer regulatory genes have changes in expression that suggest strong positive feedback by the TGFbeta pathway. In addition, many insulin-like ligand and novel genes with similarity to the extracellular domain of insulin/IGF receptors have altered expression. We have identified a large group of regulated genes with putative binding sites for the FOXO transcription factor, DAF-16. Genes with DAF-16 sites upstream of the transcription start site tend to be upregulated, whereas genes with DAF-16 sites downstream of the coding region tend to be downregulated. Finally, we also see strong regulation of many novel hedgehog- and patched-related genes, hormone biosynthetic genes, cell cycle genes, and other regulatory genes. CONCLUSIONS: The feedback regulation of insulin/IGF pathway and other dauer genes that we observe would be predicted to amplify signals from the TGFbeta pathway; this amplification may serve to ensure a decisive choice between "dauer" and "non-dauer", even if environmental cues are ambiguous. Up and down regulation of insulin-like ligands and novel genes with similarity to the extracellular domain of insulin/IGF receptors suggests opposing roles for several members of these large gene families. Unlike in adults, most genes with putative DAF-16 binding sites are upregulated during dauer entry, suggesting that DAF-16 has different activity in dauer versus adult metabolism and aging. However, our observation that the position of putative DAF-16 binding sites is correlated with the direction of regulation suggests a novel method of achieving gene-specific regulation from a single pathway. We see evidence of TGFbeta-mediated regulation of several other classes of regulatory genes, and we discuss possible functions of these genes in dauer formation.
BibTeX:
@article{Liu2004a,
  author = {Tao Liu and Karen K Zimmerman and Garth I Patterson},
  title = {Regulation of signaling genes by TGFbeta during entry into dauer diapause in C. elegans.},
  journal = {BMC Dev Biol},
  year = {2004},
  volume = {4},
  pages = {11},
  url = {http://dx.doi.org/10.1186/1471-213X-4-11},
  doi = {http://dx.doi.org/10.1186/1471-213X-4-11}
}
Lund, J., Tedesco, P., Duke, K., Wang, J., Kim, S. K. & Johnson, T. E. Transcriptional profile of aging in C. elegans. 2002 Curr Biol   whole animal  
Abstract: BACKGROUND: Numerous gerontogene mutants leading to dramatic life extensions have been identified in the nematode Caenorhabditis elegans over the last 20 years. Analysis of these mutants has provided a basis for understanding the mechanisms driving the aging process(es). Several distinct mechanisms including an altered rate of aging, increased resistance to stress, decreased metabolic rate, or alterations in a program causing organismic aging and death have been proposed to underlie these mutants. RESULTS: Whole-genome analysis of gene expression during chronological aging of the worm provides a rich database of age-specific changes in gene expression and represents one way to distinguish among these models. Using a rigorous statistical model with multiple replicates, we find that a relatively small number of genes (only 164) show statistically significant changes in transcript levels as aging occurs (<1% of the genome). Expression of heat shock proteins decreases, while expression of certain transposases increases in older worms, and these findings are consistent with a higher mortality risk due to a failure in homeostenosis and destabilization of the genome in older animals. Finally, a specific subset of genes is coordinately altered both during chronological aging and in the transition from the reproductive form to the dauer, demonstrating a mechanistic overlap in aging between these two processes. CONCLUSIONS: We have performed a whole-genome analysis of changes in gene expression during aging in C. elegans that provides a molecular description of C. elegans senescence.
BibTeX:
@article{Lund2002,
  author = {James Lund and Patricia Tedesco and Kyle Duke and John Wang and Stuart K Kim and Thomas E Johnson},
  title = {Transcriptional profile of aging in C. elegans.},
  journal = {Curr Biol},
  year = {2002},
  volume = {12},
  number = {18},
  pages = {1566--1573}
}
McCarroll, S. A., Murphy, C. T., Zou, S., Pletcher, S. D., Chin, C., Jan, Y. N., Kenyon, C., Bargmann, C. I. & Li, H. Comparing genomic expression patterns across species identifies shared transcriptional profile in aging. 2004 Nat Genet   whole animal URL  
Abstract: We developed a method for systematically comparing gene expression patterns across organisms using genome-wide comparative analysis of DNA microarray experiments. We identified analogous gene expression programs comprising shared patterns of regulation across orthologous genes. Biological features of these patterns could be identified as highly conserved subpatterns that correspond to Gene Ontology categories. Here, we demonstrate these methods by analyzing a specific biological process, aging, and show that similar analysis can be applied to a range of biological processes. We found that two highly diverged animals, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster, implement a shared adult-onset expression program of genes involved in mitochondrial metabolism, DNA repair, catabolism, peptidolysis and cellular transport. Most of these changes were implemented early in adulthood. Using this approach to search databases of gene expression data, we found conserved transcriptional signatures in larval development, embryogenesis, gametogenesis and mRNA degradation.
BibTeX:
@article{McCarroll2004,
  author = {Steven A McCarroll and Coleen T Murphy and Sige Zou and Scott D Pletcher and Chen-Shan Chin and Yuh Nung Jan and Cynthia Kenyon and Cornelia I Bargmann and Hao Li},
  title = {Comparing genomic expression patterns across species identifies shared transcriptional profile in aging.},
  journal = {Nat Genet},
  year = {2004},
  volume = {36},
  number = {2},
  pages = {197--204},
  url = {http://dx.doi.org/10.1038/ng1291},
  doi = {http://dx.doi.org/10.1038/ng1291}
}
McElwee, J. J., Schuster, E., Blanc, E., Thomas, J. H. & Gems, D. Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance. 2004 J Biol Chem   whole animal URL  
Abstract: In the nematode Caenorhabditis elegans, formation of the long-lived dauer larva and adult aging are both controlled by insulin/insulin-like growth factor-1 signaling. Potentially, increased adult life span in daf-2 insulin/insulin-like growth factor-1 receptor mutants results from mis-expression in the adult of a dauer larva longevity program. By using oligonucleotide microarray analysis, we identified a dauer transcriptional signature in daf-2 mutant adults. By means of a nonbiased statistical approach, we identified gene classes whose expression is altered similarly in dauers and daf-2 mutants, which represent potential determinants of life span. These include known determinants of longevity; the small heat shock protein/alpha-crystallins are up-regulated in both milieus. The cytochrome P450, short-chain dehydrogenase/reductase, UDP-glucuronosyltransferase, and glutathione S-transferase (in daf-2 mutants) gene classes were also up-regulated. These four gene classes act together in metabolism and excretion of toxic endobiotic and xenobiotic metabolites. This suggests that diverse toxic lipophilic and electrophilic metabolites, disposed of by phase 1 and phase 2 drug metabolism, may be the major determinants of the molecular damage that causes aging. In addition, we observed down-regulation of genes linked to nutrient uptake, including nhx-2 and pep-2. These work together in the uptake of dipeptides in the intestine, implying dietary restriction in daf-2 mutants. Some gene groups up-regulated in dauers and/or daf-2 were enriched for certain promoter elements as follows: the daf-16-binding element, the heat shock-response element, the heat shock-associated sequence, or the hif-1-response element. By contrast, the daf-16-associated element was enriched in genes down-regulated in dauers and daf-2 mutants. Thus, particular promoter elements appear longevity-associated or aging associated.
BibTeX:
@article{McElwee2004,
  author = {Joshua J McElwee and Eugene Schuster and Eric Blanc and James H Thomas and David Gems},
  title = {Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance.},
  journal = {J Biol Chem},
  year = {2004},
  volume = {279},
  number = {43},
  pages = {44533--44543},
  url = {http://dx.doi.org/10.1074/jbc.M406207200},
  doi = {http://dx.doi.org/10.1074/jbc.M406207200}
}
McGhee, J. D., Sleumer, M. C., Bilenky, M., Wong, K., McKay, S. J., Goszczynski, B., Tian, H., Krich, N. D., Khattra, J., Holt, R. A., Baillie, D. L., Kohara, Y., Marra, M. A., Jones, S. J. M., Moerman, D. G. & Robertson, A. G. The ELT-2 GATA-factor and the global regulation of transcription in the C. elegans intestine. 2007 Dev Biol   tissue specific URL  
Abstract: A SAGE library was prepared from hand-dissected intestines from adult Caenorhabditis elegans, allowing the identification of >4000 intestinally-expressed genes; this gene inventory provides fundamental information for understanding intestine function, structure and development. Intestinally-expressed genes fall into two broad classes: widely-expressed "housekeeping" genes and genes that are either intestine-specific or significantly intestine-enriched. Within this latter class of genes, we identified a subset of highly-expressed highly-validated genes that are expressed either exclusively or primarily in the intestine. Over half of the encoded proteins are candidates for secretion into the intestinal lumen to hydrolyze the bacterial food (e.g. lysozymes, amoebapores, lipases and especially proteases). The promoters of this subset of intestine-specific/intestine-enriched genes were analyzed computationally, using both a word-counting method (RSAT oligo-analysis) and a method based on Gibbs sampling (MotifSampler). Both methods returned the same over-represented site, namely an extended GATA-related sequence of the general form AHTGATAARR, which agrees with experimentally determined cis-acting control sequences found in intestine genes over the past 20 years. All promoters in the subset contain such a site, compared to <5% for control promoters; moreover, our analysis suggests that the majority (perhaps all) of genes expressed exclusively or primarily in the worm intestine are likely to contain such a site in their promoters. There are three zinc-finger GATA-type factors that are candidates to bind this extended GATA site in the differentiating C. elegans intestine: ELT-2, ELT-4 and ELT-7. All evidence points to ELT-2 being the most important of the three. We show that worms in which both the elt-4 and the elt-7 genes have been deleted from the genome are essentially wildtype, demonstrating that ELT-2 provides all essential GATA-factor functions in the intestine. The SAGE analysis also identifies more than a hundred other transcription factors in the adult intestine but few show an RNAi-induced loss-of-function phenotype and none (other than ELT-2) show a phenotype primarily in the intestine. We thus propose a simple model in which the ELT-2 GATA factor directly participates in the transcription of all intestine-specific/intestine-enriched genes, from the early embryo through to the dying adult. Other intestinal transcription factors would thus modulate the action of ELT-2, depending on the worm's nutritional and physiological needs.
BibTeX:
@article{McGhee2007,
  author = {James D McGhee and Monica C Sleumer and Mikhail Bilenky and Kim Wong and Sheldon J McKay and Barbara Goszczynski and Helen Tian and Natisha D Krich and Jaswinder Khattra and Robert A Holt and David L Baillie and Yuji Kohara and Marco A Marra and Steven J M Jones and Donald G Moerman and A. Gordon Robertson},
  title = {The ELT-2 GATA-factor and the global regulation of transcription in the C. elegans intestine.},
  journal = {Dev Biol},
  year = {2007},
  volume = {302},
  number = {2},
  pages = {627--645},
  url = {http://dx.doi.org/10.1016/j.ydbio.2006.10.024},
  doi = {http://dx.doi.org/10.1016/j.ydbio.2006.10.024}
}
Menzel, R., Bogaert, T. & Achazi, R. A systematic gene expression screen of Caenorhabditis elegans cytochrome P450 genes reveals CYP35 as strongly xenobiotic inducible. 2001 Arch Biochem Biophys   whole animal URL  
Abstract: The soil nematode Caenorhabditis elegans is one of the simplest animals having the status of a laboratory model. Its genome contains 80 cytochrome P450 genes (CYP). In order to study CYP gene expression in C. elegans mixed stages and synchronized hermaphrodites were exposed to 18 known xenobiotic cytochrome P450 inducers. Messenger RNA expression was detected by DNA arrays and semiquantitative RT-PCR. Using subfamily-specific primers, a pooled set of exon-rich CYP fragments could be amplified. In this way it was possible to systematically check the influence of different inducers on CYP expression at the same time. The well-known CYP1A inducers beta-naphthoflavone, PCB52, and lansoprazol were the most active and in particular they strongly induced almost all CYP35 isoforms. A few number of further CYP forms were found to be inducible by other xenobiotics like phenobarbital, atrazine, and clofibrate. In addition, a transgenic C. elegans line expressing GFP under control of the CYP35A2 promoter showed a strong induction of the fusion by beta-naphthoflavone in the intestine.
BibTeX:
@article{Menzel2001,
  author = {R. Menzel and T. Bogaert and R. Achazi},
  title = {A systematic gene expression screen of Caenorhabditis elegans cytochrome P450 genes reveals CYP35 as strongly xenobiotic inducible.},
  journal = {Arch Biochem Biophys},
  year = {2001},
  volume = {395},
  number = {2},
  pages = {158--168},
  url = {http://dx.doi.org/10.1006/abbi.2001.2568},
  doi = {http://dx.doi.org/10.1006/abbi.2001.2568}
}
Murphy, C. T., McCarroll, S. A., Bargmann, C. I., Fraser, A., Kamath, R. S., Ahringer, J., Li, H. & Kenyon, C. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. 2003 Nature   whole animal URL  
Abstract: Ageing is a fundamental, unsolved mystery in biology. DAF-16, a FOXO-family transcription factor, influences the rate of ageing of Caenorhabditis elegans in response to insulin/insulin-like growth factor 1 (IGF-I) signalling. Using DNA microarray analysis, we have found that DAF-16 affects expression of a set of genes during early adulthood, the time at which this pathway is known to control ageing. Here we find that many of these genes influence the ageing process. The insulin/IGF-I pathway functions cell non-autonomously to regulate lifespan, and our findings suggest that it signals other cells, at least in part, by feedback regulation of an insulin/IGF-I homologue. Furthermore, our findings suggest that the insulin/IGF-I pathway ultimately exerts its effect on lifespan by upregulating a wide variety of genes, including cellular stress-response, antimicrobial and metabolic genes, and by downregulating specific life-shortening genes.
BibTeX:
@article{Murphy2003,
  author = {Coleen T Murphy and Steven A McCarroll and Cornelia I Bargmann and Andrew Fraser and Ravi S Kamath and Julie Ahringer and Hao Li and Cynthia Kenyon},
  title = {Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans.},
  journal = {Nature},
  year = {2003},
  volume = {424},
  number = {6946},
  pages = {277--283},
  url = {http://dx.doi.org/10.1038/nature01789},
  doi = {http://dx.doi.org/10.1038/nature01789}
}
Pauli, F., Liu, Y., Kim, Y. A., Chen, P. & Kim, S. K. Chromosomal clustering and GATA transcriptional regulation of intestine-expressed genes in C. elegans. 2006 Development   tissue-specific URL  
Abstract: We used mRNA tagging to identify genes expressed in the intestine of C. elegans. Animals expressing an epitope-tagged protein that binds the poly-A tail of mRNAs (FLAG::PAB-1) from an intestine-specific promoter (ges-1) were used to immunoprecipitate FLAG::PAB-1/mRNA complexes from the intestine. A total of 1938 intestine-expressed genes (P<0.001) were identified using DNA microarrays. First, we compared the intestine-expressed genes with those expressed in the muscle and germline, and identified 510 genes enriched in all three tissues and 624 intestine-, 230 muscle- and 1135 germ line-enriched genes. Second, we showed that the 1938 intestine-expressed genes were physically clustered on the chromosomes, suggesting that the order of genes in the genome is influenced by the effect of chromatin domains on gene expression. Furthermore, the commonly expressed genes showed more chromosomal clustering than the tissue-enriched genes, suggesting that chromatin domains may influence housekeeping genes more than tissue-specific genes. Third, in order to gain further insight into the regulation of intestinal gene expression, we searched for regulatory motifs. This analysis found that the promoters of the intestine genes were enriched for the GATA transcription factor consensus binding sequence. We experimentally verified these results by showing that the GATA motif is required in cis and that GATA transcription factors are required in trans for expression of these intestinal genes.
BibTeX:
@article{Pauli2006,
  author = {Florencia Pauli and Yueyi Liu and Yoona A Kim and Pei-Jiun Chen and Stuart K Kim},
  title = {Chromosomal clustering and GATA transcriptional regulation of intestine-expressed genes in C. elegans.},
  journal = {Development},
  year = {2006},
  volume = {133},
  number = {2},
  pages = {287--295},
  url = {http://dx.doi.org/10.1242/dev.02185},
  doi = {http://dx.doi.org/10.1242/dev.02185}
}
Portman, D. S. & Emmons, S. W. Identification of C. elegans sensory ray genes using whole-genome expression profiling. 2004 Dev Biol   tissue specific URL  
Abstract: The three cells that comprise each C. elegans sensory ray (two sensory neurons and a structural cell) descend from a single neuroblast precursor cell. The atonal ortholog lin-32 and the E/daughterless ortholog hlh-2 act to confer neural competence during ray development, but additional regulatory factors that control specific aspects of cell fate are largely unknown. Here, we use full-genome DNA microarrays to compare gene expression profiles in adult males of two mutant strains to identify new components of the regulatory network that controls ray development and function. This approach identified a large set of candidate ray genes. Using reporter genes, we confirmed ray expression for 13 of these, including a beta-tubulin, a TWK-family channel, a putative chemoreceptor and four novel genes (the cwp genes) with a potential role in sensory signaling through the C. elegans polycystins lov-1 and pkd-2. Additionally, we have found several ray-expressed transcription factors, including the Zn-finger factor egl-46 and the bHLH gene hlh-10. The expression of many of these genes requires lin-32 function, though this requirement may not reflect direct activation by lin-32. Our strategy provides a complementary foundation for modeling the genetic network that controls the development of a simple sensory organ.
BibTeX:
@article{Portman2004,
  author = {Douglas S Portman and Scott W Emmons},
  title = {Identification of C. elegans sensory ray genes using whole-genome expression profiling.},
  journal = {Dev Biol},
  year = {2004},
  volume = {270},
  number = {2},
  pages = {499--512},
  url = {http://dx.doi.org/10.1016/j.ydbio.2004.02.020},
  doi = {http://dx.doi.org/10.1016/j.ydbio.2004.02.020}
}
Reichert, K. & Menzel, R. Expression profiling of five different xenobiotics using a Caenorhabditis elegans whole genome microarray. 2005 Chemosphere   whole animal URL  
Abstract: The soil nematode Caenorhabditis elegans is frequently used in ecotoxicological studies due to its wide distribution in terrestrial habitats, its easy handling in the laboratory, and its sensitivity against different kinds of stress. Since its genome has been completely sequenced, more and more studies are investigating the functional relation of gene expression and phenotypic response. For these reasons C. elegans seems to be an attractive animal for the development of a new, genome based, ecotoxicological test system. In recent years, the DNA array technique has been established as a powerful tool to obtain distinct gene expression patterns in response to different experimental conditions. Using a C. elegans whole genome DNA microarray in this study, the effects of five different xenobiotics on the gene expression of the nematode were investigated. The exposure time for the following five applied compounds beta-NF (5 mg/l), Fla (0.5 mg/l), atrazine (25 mg/l), clofibrate (10 mg/l) and DES (0.5 mg/l) was 48+/-5 h. The analysis of the data showed a clear induction of 203 genes belonging to different families like the cytochromes P450, UDP-glucoronosyltransferases (UDPGT), glutathione S-transferases (GST), carboxylesterases, collagenes, C-type lectins and others. Under the applied conditions, fluoranthene was able to induce most of the induceable genes, followed by clofibrate, atrazine, beta-naphthoflavone and diethylstilbestrol. A decreased expression could be shown for 153 genes with atrazine having the strongest effect followed by fluoranthene, diethylstilbestrol, beta-naphthoflavone and clofibrate. For upregulated genes a change ranging from approximately 2.1- till 42.3-fold and for downregulated genes from approximately 2.1 till 6.6-fold of gene expression could be affected through the applied xenobiotics. The results confirm the applicability of the gene expression for the development of an ecotoxicological test system. Compared to classical tests the main advantages of this new approach will be the increased sensitivity and it's potential for a substance class specific effect determination as well as the large numbers of genes that can be screened rapidly at the same time and the selection of well regulated marker genes to study more in detail.
BibTeX:
@article{Reichert2005,
  author = {Kerstin Reichert and Ralph Menzel},
  title = {Expression profiling of five different xenobiotics using a Caenorhabditis elegans whole genome microarray.},
  journal = {Chemosphere},
  year = {2005},
  volume = {61},
  number = {2},
  pages = {229--237},
  url = {http://dx.doi.org/10.1016/j.chemosphere.2005.01.077},
  doi = {http://dx.doi.org/10.1016/j.chemosphere.2005.01.077}
}
Reinke, V., Gil, I. S., Ward, S. & Kazmer, K. Genome-wide germline-enriched and sex-biased expression profiles in Caenorhabditis elegans. 2004 Development   tissue-specific URL  
Abstract: We performed a genome-wide analysis of gene expression in C. elegans to identify germline- and sex-regulated genes. Using mutants that cause defects in germ cell proliferation or gametogenesis, we identified sets of genes with germline-enriched expression in either hermaphrodites or males, or in both sexes. Additionally, we compared gene expression profiles between males and hermaphrodites lacking germline tissue to define genes with sex-biased expression in terminally differentiated somatic tissues. Cross-referencing hermaphrodite germline and somatic gene sets with in situ hybridization data demonstrates that the vast majority of these genes have appropriate spatial expression patterns. Additionally, we examined gene expression at multiple times during wild-type germline development to define temporal expression profiles for these genes. Sex- and germline-regulated genes have a non-random distribution in the genome, with especially strong biases for and against the X chromosome. Comparison with data from large-scale RNAi screens demonstrates that genes expressed in the oogenic germline display visible phenotypes more frequently than expected.
BibTeX:
@article{Reinke2004,
  author = {Valerie Reinke and Inigo San Gil and Samuel Ward and Keith Kazmer},
  title = {Genome-wide germline-enriched and sex-biased expression profiles in Caenorhabditis elegans.},
  journal = {Development},
  year = {2004},
  volume = {131},
  number = {2},
  pages = {311--323},
  url = {http://dx.doi.org/10.1242/dev.00914},
  doi = {http://dx.doi.org/10.1242/dev.00914}
}
Romagnolo, B., Jiang, M., Kiraly, M., Breton, C., Begley, R., Wang, J., Lund, J. & Kim, S. K. Downstream targets of let-60 Ras in Caenorhabditis elegans. 2002 Dev Biol   whole animal URL  
Abstract: In Caenorhabditis elegans, let-60 Ras controls many cellular processes, such as differentiation of vulval epithelial cells, function of chemosensory neurons, and meiotic progression in the germ line. Although much is known about the let-60 Ras signaling pathway, relatively little is understood about the target genes induced by let-60 Ras signaling that carry out terminal effector functions leading to morphological change. We have used DNA microarrays to identify 708 genes that change expression in response to activated let-60 Ras.
BibTeX:
@article{Romagnolo2002,
  author = {BĂ©atrice Romagnolo and Min Jiang and Moni Kiraly and Carrie Breton and Rebecca Begley and John Wang and James Lund and Stuart K Kim},
  title = {Downstream targets of let-60 Ras in Caenorhabditis elegans.},
  journal = {Dev Biol},
  year = {2002},
  volume = {247},
  number = {1},
  pages = {127--136},
  url = {http://dx.doi.org/10.1006/dbio.2002.0692},
  doi = {http://dx.doi.org/10.1006/dbio.2002.0692}
}
Roy, P. J., Stuart, J. M., Lund, J. & Kim, S. K. Chromosomal clustering of muscle-expressed genes in Caenorhabditis elegans. 2002 Nature   tissue-specific URL  
Abstract: Chromosomes are divided into domains of open chromatin, where genes have the potential to be expressed, and domains of closed chromatin, where genes are not expressed. Classic examples of open chromatin domains include 'puffs' on polytene chromosomes in Drosophila and extended loops from lampbrush chromosomes. If multiple genes were typically expressed together from a single open chromatin domain, the position of co-expressed genes along the chromosomes would appear clustered. To investigate whether co-expressed genes are clustered, we examined the chromosomal positions of the genes expressed in the muscle of Caenorhabditis elegans at the first larval stage. Here we show that co-expressed genes in C. elegans are clustered in groups of 2-5 along the chromosomes, suggesting that expression from a chromatin domain can extend over several genes. These observations reveal a higher-order organization of the structure of the genome, in which the order of the genes along the chromosome id correlated with their expression in specific tissues.
BibTeX:
@article{Roy2002,
  author = {Peter J Roy and Joshua M Stuart and Jim Lund and Stuart K Kim},
  title = {Chromosomal clustering of muscle-expressed genes in Caenorhabditis elegans.},
  journal = {Nature},
  year = {2002},
  volume = {418},
  number = {6901},
  pages = {975--979},
  url = {http://dx.doi.org/10.1038/nature01012},
  doi = {http://dx.doi.org/10.1038/nature01012}
}
Shapira, M., Hamlin, B. J., Rong, J., Chen, K., Ronen, M. & Tan, M. A conserved role for a GATA transcription factor in regulating epithelial innate immune responses. 2006 Proc Natl Acad Sci U S A   whole animal URL  
Abstract: Innate immunity is an ancient and conserved defense mechanism. Although host responses toward various pathogens have been delineated, how these responses are orchestrated in a whole animal is less understood. Through an unbiased genome-wide study performed in Caenorhabditis elegans, we identified a conserved function for endodermal GATA transcription factors in regulating local epithelial innate immune responses. Gene expression and functional RNAi-based analyses identified the tissue-specific GATA transcription factor ELT-2 as a major regulator of an early intestinal protective response to infection with the human bacterial pathogen Pseudomonas aeruginosa. In the adult worm, ELT-2 is required specifically for infection responses and survival on pathogen but makes no significant contribution to gene expression associated with intestinal maintenance or to resistance to cadmium, heat, and oxidative stress. We further demonstrate that this function is conserved, because the human endodermal transcription factor GATA6 has a protective function in lung epithelial cells exposed to P. aeruginosa. These findings expand the repertoire of innate immunity mechanisms and illuminate a yet-unknown function of endodermal GATA proteins.
BibTeX:
@article{Shapira2006,
  author = {Michael Shapira and Brigham J Hamlin and Jiming Rong and Karen Chen and Michal Ronen and Man-Wah Tan},
  title = {A conserved role for a GATA transcription factor in regulating epithelial innate immune responses.},
  journal = {Proc Natl Acad Sci U S A},
  year = {2006},
  volume = {103},
  number = {38},
  pages = {14086--14091},
  url = {http://dx.doi.org/10.1073/pnas.0603424103},
  doi = {http://dx.doi.org/10.1073/pnas.0603424103}
}
Shen, C., Nettleton, D., Jiang, M., Kim, S. K. & Powell-Coffman, J. A. Roles of the HIF-1 hypoxia-inducible factor during hypoxia response in Caenorhabditis elegans. 2005 J Biol Chem   whole animal URL  
Abstract: The human hypoxia-inducible transcription factor HIF-1 is a critical regulator of cellular and systemic responses to low oxygen levels. When oxygen levels are high, the HIF-1alpha subunit is hydroxylated and is targeted for degradation by the von Hippel-Lindau tumor suppressor protein (VHL). This regulatory pathway is evolutionarily conserved, and the Caenorhabditis elegans hif-1 and vhl-1 genes encode homologs of the HIF-1alpha subunit and VHL. To understand and describe more fully the molecular basis for hypoxia response in this important genetic model system, we compared hypoxia-induced changes in mRNA expression in wild-type, hif-1-deficient, and vhl-1-deficient C. elegans using whole genome microarrays. These studies identified 110 hypoxia-regulated gene expression changes, 63 of which require hif-1 function. Mutation of vhl-1 abrogates most hif-1-dependent changes in mRNA expression. Genes regulated by C. elegans hif-1 have predicted functions in signal transduction, metabolism, transport, and extracellular matrix remodeling. We examined the in vivo requirement for 16 HIF-1 target genes and discovered that the phy-2 prolyl 4-hydroxylase alpha subunit is critical for survival in hypoxic conditions. Some HIF-1 target genes negatively regulate formation of stress-resistant dauer larvae. The microarray data presented herein also provide clear evidence for an HIF-1-independent pathway for hypoxia response, and this pathway regulates the expression of multiple heat shock proteins and several transcription factors.
BibTeX:
@article{Shen2005a,
  author = {Chuan Shen and Daniel Nettleton and Min Jiang and Stuart K Kim and Jo Anne Powell-Coffman},
  title = {Roles of the HIF-1 hypoxia-inducible factor during hypoxia response in Caenorhabditis elegans.},
  journal = {J Biol Chem},
  year = {2005},
  volume = {280},
  number = {21},
  pages = {20580--20588},
  url = {http://dx.doi.org/10.1074/jbc.M501894200},
  doi = {http://dx.doi.org/10.1074/jbc.M501894200}
}
Shen, X., Ellis, R. E., Sakaki, K. & Kaufman, R. J. Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans. 2005 PLoS Genet   whole animal URL  
Abstract: The unfolded protein response (UPR) is an adaptive signaling pathway utilized to sense and alleviate the stress of protein folding in the endoplasmic reticulum (ER). In mammals, the UPR is mediated through three proximal sensors PERK/PEK, IRE1, and ATF6. PERK/PEK is a protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 to inhibit protein synthesis. Activation of IRE1 induces splicing of XBP1 mRNA to produce a potent transcription factor. ATF6 is a transmembrane transcription factor that is activated by cleavage upon ER stress. We show that in Caenorhabditis elegans, deletion of either ire-1 or xbp-1 is synthetically lethal with deletion of either atf-6 or pek-1, both producing a developmental arrest at larval stage 2. Therefore, in C. elegans, atf-6 acts synergistically with pek-1 to complement the developmental requirement for ire-1 and xbp-1. Microarray analysis identified inducible UPR (i-UPR) genes, as well as numerous constitutive UPR (c-UPR) genes that require the ER stress transducers during normal development. Although ire-1 and xbp-1 together regulate transcription of most i-UPR genes, they are each required for expression of nonoverlapping sets of c-UPR genes, suggesting that they have distinct functions. Intriguingly, C. elegans atf-6 regulates few i-UPR genes following ER stress, but is required for the expression of many c-UPR genes, indicating its importance during development and homeostasis. In contrast, pek-1 is required for induction of approximately 23% of i-UPR genes but is dispensable for the c-UPR. As pek-1 and atf-6 mainly act through sets of nonoverlapping targets that are different from ire-1 and xbp-1 targets, at least two coordinated responses are required to alleviate ER stress by distinct mechanisms. Finally, our array study identified the liver-specific transcription factor CREBh as a novel UPR gene conserved during metazoan evolution.
BibTeX:
@article{Shen2005,
  author = {Xiaohua Shen and Ronald E Ellis and Kenjiro Sakaki and Randal J Kaufman},
  title = {Genetic interactions due to constitutive and inducible gene regulation mediated by the unfolded protein response in C. elegans.},
  journal = {PLoS Genet},
  year = {2005},
  volume = {1},
  number = {3},
  pages = {e37},
  url = {http://dx.doi.org/10.1371/journal.pgen.0010037},
  doi = {http://dx.doi.org/10.1371/journal.pgen.0010037}
}
Stetina, S. E. V., Watson, J. D., Fox, R. M., Olszewski, K. L., Spencer, W. C., Roy, P. J. & Miller, D. M. Cell-specific microarray profiling experiments reveal a comprehensive picture of gene expression in the C. elegans nervous system. 2007 Genome Biol   tissue-specific URL  
Abstract: BACKGROUND: With its fully sequenced genome and simple, well-defined nervous system, the nematode Caenorhabditis elegans offers a unique opportunity to correlate gene expression with neuronal differentiation. The lineal origin, cellular morphology and synaptic connectivity of each of the 302 neurons are known. In many instances, specific behaviors can be attributed to particular neurons or circuits. Here we describe microarray-based methods that monitor gene expression in C. elegans neurons and, thereby, link comprehensive profiles of neuronal transcription to key developmental and functional properties of the nervous system. RESULTS: We employed complementary microarray-based strategies to profile gene expression in the embryonic and larval nervous systems. In the MAPCeL (Microarray Profiling C. elegans cells) method, we used fluorescence activated cell sorting (FACS) to isolate GFP-tagged embryonic neurons for microarray analysis. To profile the larval nervous system, we used the mRNA-tagging technique in which an epitope-labeled mRNA binding protein (FLAG-PAB-1) was transgenically expressed in neurons for immunoprecipitation of cell-specific transcripts. These combined approaches identified approximately 2,500 mRNAs that are highly enriched in either the embryonic or larval C. elegans nervous system. These data are validated in part by the detection of gene classes (for example, transcription factors, ion channels, synaptic vesicle components) with established roles in neuronal development or function. Of particular interest are 19 conserved transcripts of unknown function that are also expressed in the mammalian brain. In addition to utilizing these profiling approaches to define stage-specific gene expression, we also applied the mRNA-tagging method to fingerprint a specific neuron type, the A-class group of cholinergic motor neurons, during early larval development. A comparison of these data to a MAPCeL profile of embryonic A-class motor neurons identified genes with common functions in both types of A-class motor neurons as well as transcripts with roles specific to each motor neuron type. CONCLUSION: We describe microarray-based strategies for generating expression profiles of embryonic and larval C. elegans neurons. These methods can be applied to particular neurons at specific developmental stages and, therefore, provide an unprecedented opportunity to obtain spatially and temporally defined snapshots of gene expression in a simple model nervous system.
BibTeX:
@article{Stetina2007,
  author = {Stephen E Von Stetina and Joseph D Watson and Rebecca M Fox and Kellen L Olszewski and W. Clay Spencer and Peter J Roy and David M Miller},
  title = {Cell-specific microarray profiling experiments reveal a comprehensive picture of gene expression in the C. elegans nervous system.},
  journal = {Genome Biol},
  year = {2007},
  volume = {8},
  number = {7},
  pages = {R135},
  url = {http://dx.doi.org/10.1186/gb-2007-8-7-r135},
  doi = {http://dx.doi.org/10.1186/gb-2007-8-7-r135}
}
Szewczyk, N. J., Udranszky, I. A., Kozak, E., Sunga, J., Kim, S. K., Jacobson, L. A. & Conley, C. A. Delayed development and lifespan extension as features of metabolic lifestyle alteration in C. elegans under dietary restriction. 2006 J Exp Biol   whole animal URL  
Abstract: Studies of the model organism Caenorhabditis elegans have almost exclusively utilized growth on a bacterial diet. Such culturing presents a challenge to automation of experimentation and introduces bacterial metabolism as a secondary concern in drug and environmental toxicology studies. Axenic cultivation of C. elegans can avoid these problems, yet past work suggests that axenic growth is unhealthy for C. elegans. Here we employ a chemically defined liquid medium to culture C. elegans and find development slows, fecundity declines, lifespan increases, lipid and protein stores decrease, and gene expression changes relative to that on a bacterial diet. These changes do not appear to be random pathologies associated with malnutrition, as there are no developmental delays associated with starvation, such as L1 or dauer diapause. Additionally, development and reproductive period are fixed percentages of lifespan regardless of diet, suggesting that these alterations are adaptive. We propose that C. elegans can exist as a healthy animal with at least two distinct adult life histories. One life history maximizes the intrinsic rate of population increase, the other maximizes the efficiency of exploitation of the carrying capacity of the environment. Microarray analysis reveals increased transcript levels of daf-16 and downstream targets and past experiments demonstrate that DAF-16 (FOXO) acting on downstream targets can influence all of the phenotypes we see altered in maintenance medium. Thus, life history alteration in response to diet may be modulated by DAF-16. Our observations introduce a powerful system for automation of experimentation on healthy C. elegans and for systematic analysis of the profound impact of diet on animal physiology.
BibTeX:
@article{Szewczyk2006,
  author = {Nathaniel J Szewczyk and Ingrid A Udranszky and Elena Kozak and June Sunga and Stuart K Kim and Lewis A Jacobson and Catharine A Conley},
  title = {Delayed development and lifespan extension as features of metabolic lifestyle alteration in C. elegans under dietary restriction.},
  journal = {J Exp Biol},
  year = {2006},
  volume = {209},
  number = {Pt 20},
  pages = {4129--4139},
  url = {http://dx.doi.org/10.1242/jeb.02492},
  doi = {http://dx.doi.org/10.1242/jeb.02492}
}
Troemel, E. R., Chu, S. W., Reinke, V., Lee, S. S., Ausubel, F. M. & Kim, D. H. p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans. 2006 PLoS Genet   whole animal URL  
Abstract: The PMK-1 p38 mitogen-activated protein kinase pathway and the DAF-2-DAF-16 insulin signaling pathway control Caenorhabditis elegans intestinal innate immunity. pmk-1 loss-of-function mutants have enhanced sensitivity to pathogens, while daf-2 loss-of-function mutants have enhanced resistance to pathogens that requires upregulation of the DAF-16 transcription factor. We used genetic analysis to show that the pathogen resistance of daf-2 mutants also requires PMK-1. However, genome-wide microarray analysis indicated that there was essentially no overlap between genes positively regulated by PMK-1 and DAF-16, suggesting that they form parallel pathways to promote immunity. We found that PMK-1 controls expression of candidate secreted antimicrobials, including C-type lectins, ShK toxins, and CUB-like genes. Microarray analysis demonstrated that 25% of PMK-1 positively regulated genes are induced by Pseudomonas aeruginosa infection. Using quantitative PCR, we showed that PMK-1 regulates both basal and infection-induced expression of pathogen response genes, while DAF-16 does not. Finally, we used genetic analysis to show that PMK-1 contributes to the enhanced longevity of daf-2 mutants. We propose that the PMK-1 pathway is a specific, indispensable immunity pathway that mediates expression of secreted immune response genes, while the DAF-2-DAF-16 pathway appears to regulate immunity as part of a more general stress response. The contribution of the PMK-1 pathway to the enhanced lifespan of daf-2 mutants suggests that innate immunity is an important determinant of longevity.
BibTeX:
@article{Troemel2006,
  author = {Emily R Troemel and Stephanie W Chu and Valerie Reinke and Siu Sylvia Lee and Frederick M Ausubel and Dennis H Kim},
  title = {p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans.},
  journal = {PLoS Genet},
  year = {2006},
  volume = {2},
  number = {11},
  pages = {e183},
  url = {http://dx.doi.org/10.1371/journal.pgen.0020183},
  doi = {http://dx.doi.org/10.1371/journal.pgen.0020183}
}
Urano, F., Calfon, M., Yoneda, T., Yun, C., Kiraly, M., Clark, S. G. & Ron, D. A survival pathway for Caenorhabditis elegans with a blocked unfolded protein response. 2002 J Cell Biol   whole animal URL  
Abstract: The unfolded protein response (UPR) counteracts stress caused by unprocessed ER client proteins. A genome-wide survey showed impaired induction of many UPR target genes in xbp-1 mutant Caenorhabditis elegans that are unable to signal in the highly conserved IRE1-dependent UPR pathway. However a family of genes, abu (activated in blocked UPR), was induced to higher levels in ER-stressed xbp-1 mutant animals than in ER-stressed wild-type animals. RNA-mediated interference (RNAi) inactivation of a representative abu family member, abu-1 (AC3.3), activated the ER stress marker hsp-4::gfp in otherwise normal animals and killed 50% of ER-stressed ire-1 and xbp-1 mutant animals. Abu-1(RNAi) also enhanced the effect of inactivation of sel-1, an ER-associated protein degradation gene. The nine abu genes encode highly related type I transmembrane proteins whose lumenal domains have sequence similarity to a mammalian cell surface scavenger receptor of endothelial cells that binds chemically modified extracellular proteins and directs their lysosomal degradation. Our findings that ABU-1 is an intracellular protein located within the endomembrane system that is induced by ER stress in xbp-1 mutant animals suggest that ABU proteins may interact with abnormal ER client proteins and this function may be particularly important in animals with an impaired UPR.
BibTeX:
@article{Urano2002,
  author = {Fumihiko Urano and Marcella Calfon and Takunari Yoneda and Chi Yun and Moni Kiraly and Scott G Clark and David Ron},
  title = {A survival pathway for Caenorhabditis elegans with a blocked unfolded protein response.},
  journal = {J Cell Biol},
  year = {2002},
  volume = {158},
  number = {4},
  pages = {639--646},
  url = {http://dx.doi.org/10.1083/jcb.200203086},
  doi = {http://dx.doi.org/10.1083/jcb.200203086}
}
Viswanathan, M., Kim, S. K., Berdichevsky, A. & Guarente, L. A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. 2005 Dev Cell   whole animal URL  
Abstract: C. elegans SIR-2.1, a member of the Sir-2 family of NAD(+)-dependent protein deacetylases, has been shown to regulate nematode aging via the insulin/IGF pathway transcription factor daf-16. Treatment of C. elegans with the small molecule resveratrol, however, extends life span in a manner fully dependent upon sir-2.1, but independent of daf-16. Microarray analysis of worms treated with resveratrol demonstrates the transcriptional induction of a family of genes encoding prion-like glutamine/asparagine-rich proteins involved in endoplasmic reticulum (ER) stress response to unfolded proteins. RNA interference of abu-11, a member of this ER stress gene family, abolishes resveratrol-mediated life span extension, and overexpression of abu-11 extends the life span of transgenic animals. Furthermore, SIR-2.1 normally represses transcription of abu-11 and other ER stress gene family members, indicating that resveratrol extends life span by inhibiting sir-2.1-mediated repression of ER stress genes. Our findings demonstrate that abu-11 and other members of its ER stress gene family are positive determinants of C. elegans life span.
BibTeX:
@article{Viswanathan2005,
  author = {Mohan Viswanathan and Stuart K Kim and Ala Berdichevsky and Leonard Guarente},
  title = {A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span.},
  journal = {Dev Cell},
  year = {2005},
  volume = {9},
  number = {5},
  pages = {605--615},
  url = {http://dx.doi.org/10.1016/j.devcel.2005.09.017},
  doi = {http://dx.doi.org/10.1016/j.devcel.2005.09.017}
}
Wang, J. & Kim, S. K. Global analysis of dauer gene expression in Caenorhabditis elegans. 2003 Development   whole animal  
Abstract: The dauer is a developmental stage in C. elegans that exhibits increased longevity, stress resistance, nictation and altered metabolism compared with normal worms. We have used DNA microarrays to profile gene expression differences during the transition from the dauer state to the non-dauer state and after feeding of starved L1 animals, and have identified 1984 genes that show significant expression changes. This analysis includes genes that encode transcription factors and components of signaling pathways that could regulate the entry to and exit from the dauer state, and genes that encode components of metabolic pathways important for dauer survival and longevity. Homologs of C. elegans dauer-enriched genes may be involved in the disease process in parasitic nematodes.
BibTeX:
@article{Wang2003,
  author = {John Wang and Stuart K Kim},
  title = {Global analysis of dauer gene expression in Caenorhabditis elegans.},
  journal = {Development},
  year = {2003},
  volume = {130},
  number = {8},
  pages = {1621--1634}
}
Wang, P., Zhao, J. & Corsi, A. K. Identification of novel target genes of CeTwist and CeE/DA. 2006 Dev Biol   whole animal URL  
Abstract: Twist, a basic helix-loop-helix (bHLH) transcription factor, plays an important role in mesoderm development in many organisms, including C. elegans where CeTwist is required to direct cell fate specifications of a subset of mesodermal cells. Although several target genes of CeTwist have been identified, how this protein accomplishes its function is unclear. In addition, several human genes whose mutations cause different syndromes of craniosynostosis (premature fusion of cranial sutures) have homologues in the CeTwist pathway. Identification of novel target genes of CeTwist will shed more light on the functions of CeTwist in mesoderm development, and the corresponding human homologues will be good candidates for related syndromes with unidentified mutated genes. In our study, both CeTwist and its heterodimeric partner, CeE/DA, were overexpressed from the inducible heat-shock promoter, and potential target genes were detected with Affymetrix oligonucleotide microarrays. Using transcriptional GFP reporters, we found 11 genes were expressed in cells coincident with known CeTwist target gene products. Based on subsequent validation experiments, 9 genes were defined as novel CeTwist and CeE/DA targets. Human homologues of two of these genes might be involved in craniofacial diseases, which further validates C. elegans as a good model organism for providing insights into these disorders.
BibTeX:
@article{Wang2006,
  author = {Peng Wang and Jie Zhao and Ann K Corsi},
  title = {Identification of novel target genes of CeTwist and CeE/DA.},
  journal = {Dev Biol},
  year = {2006},
  volume = {293},
  number = {2},
  pages = {486--498},
  url = {http://dx.doi.org/10.1016/j.ydbio.2005.10.011},
  doi = {http://dx.doi.org/10.1016/j.ydbio.2005.10.011}
}
Zhang, Y., Ma, C., Delohery, T., Nasipak, B., Foat, B. C., Bounoutas, A., Bussemaker, H. J., Kim, S. K. & Chalfie, M. Identification of genes expressed in C. elegans touch receptor neurons. 2002 Nature   tissue-specific URL  
Abstract: The extent of gene regulation in cell differentiation is poorly understood. We previously used saturation mutagenesis to identify 18 genes that are needed for the development and function of a single type of sensory neuron--the touch receptor neuron for gentle touch in Caenorhabditis elegans. One of these genes, mec-3, encodes a transcription factor that controls touch receptor differentiation. By culturing and isolating wild-type and mec-3 mutant cells from embryos and applying their amplified RNA to DNA microarrays, here we have identified genes that are known to be expressed in touch receptors, a previously uncloned gene (mec-17) that is needed for maintaining touch receptor differentiation, and more than 50 previously unknown mec-3-dependent genes. These genes are randomly distributed in the genome and under-represented both for genes that are co-expressed in operons and for multiple members of gene families. Using regions 5' of the start codon of the first 20 genes, we have also identified an over-represented heptanucleotide, AATGCAT, that is needed for the expression of touch receptor genes.
BibTeX:
@article{Zhang2002a,
  author = {Yun Zhang and Charles Ma and Thomas Delohery and Brian Nasipak and Barrett C Foat and Alexander Bounoutas and Harmen J Bussemaker and Stuart K Kim and Martin Chalfie},
  title = {Identification of genes expressed in C. elegans touch receptor neurons.},
  journal = {Nature},
  year = {2002},
  volume = {418},
  number = {6895},
  pages = {331--335},
  url = {http://dx.doi.org/10.1038/nature00891},
  doi = {http://dx.doi.org/10.1038/nature00891}
}

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