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1.  Gene-centered regulatory networks 
Differential gene expression plays a critical role in the development and physiology of multicellular organisms. At a ‘systems level’ (e.g. at the level of a tissue, organ or whole organism), this process can be studied using gene regulatory network (GRN) models that capture physical and regulatory interactions between genes and their regulators. In the past years, significant progress has been made toward the mapping of GRNs using a variety of experimental and computational approaches. Here, we will discuss gene-centered approaches that we employed to characterize GRNs and describe insights that we have obtained into the global design principles of gene regulation in complex metazoan systems.
PMCID: PMC3096532  PMID: 20008400
transcription factor; differential gene expression; gene-centered; gene regulatory network; yeast one-hybrid assay; Caenorhabditis elegans
2.  Gene regulatory networks governing pancreas development 
Developmental cell  2013;25(1):5-13.
Elucidation of cellular and gene regulatory networks (GRNs) governing organ development will accelerate progress toward tissue replacement. Here, we have compiled reference GRNs underlying pancreas development from data mining that integrates multiple approaches including mutant analysis, lineage tracing, cell purification, gene expression and enhancer analysis, and biochemical studies of gene regulation. Using established computational tools, we integrated and represented these networks into frameworks that should enhance understanding of the surging output of genomic-scale genetic and epigenetic studies of pancreas development and diseases like diabetes and pancreatic cancer. We envision similar approaches would be useful for understanding development of other organs.
PMCID: PMC3645877  PMID: 23597482
3.  Diet-Induced Developmental Acceleration Independent of TOR and Insulin in C. elegans 
Cell  2013;153(1):10.1016/j.cell.2013.02.049.
Dietary composition has major effects on physiology. Here we show that developmental rate, reproduction and lifespan are altered in C. elegans fed Comamonas DA1877 relative to those fed a standard E. coli OP50 diet. We identify a set of genes that change in expression in response to this diet, and use the promoter of one of these (acdh-1) as a dietary sensor. Remarkably, the effects on transcription and development occur even when Comamonas DA1877 is diluted with another diet, suggesting that Comamonas DA1877 generates a signal that is sensed by the nematode. Surprisingly, the developmental effect is independent from TOR and insulin signaling. Rather, Comamonas DA1877 affects cyclic gene expression during molting, likely through the nuclear hormone receptor NHR-23. Altogether, our findings indicate that different bacteria elicit various responses via distinct mechanisms, which has implications for diseases such as obesity and the interactions between the human microbiome and intestinal cells.
PMCID: PMC3821073  PMID: 23540701
4.  Integration of Metabolic and Gene Regulatory Networks Modulates The C. elegans Dietary Response 
Cell  2013;153(1):10.1016/j.cell.2013.02.050.
Expression profiles are tailored according to dietary input. However, the networks that control dietary responses remain largely uncharacterized. Here, we combine forward and reverse genetic screens to delineate a network of 184 genes that affect the C. elegans dietary response to Comamonas DA1877 bacteria. We find that perturbation of a mitochondrial network comprised of enzymes involved in amino acid metabolism and the TCA cycle affects the dietary response. In humans, mutations in the corresponding genes cause inborn diseases of amino acid metabolism, most of which are treated by dietary intervention. We identify several transcription factors (TFs) that mediate the changes in gene expression upon metabolic network perturbations. Altogether, our findings unveil a transcriptional response system that is poised to sense dietary cues and metabolic imbalances, illustrating extensive communication between metabolic networks in the mitochondria and gene regulatory networks in the nucleus.
PMCID: PMC3817025  PMID: 23540702
5.  Functional modularity of nuclear hormone receptors in a Caenorhabditis elegans metabolic gene regulatory network 
We present the first gene regulatory network (GRN) that pertains to post-developmental gene expression. Specifically, we mapped a transcription regulatory network of Caenorhabditis elegans metabolic gene promoters using gene-centered yeast one-hybrid assays. We found that the metabolic GRN is enriched for nuclear hormone receptors (NHRs) compared with other gene-centered regulatory networks, and that these NHRs organize into functional network modules.The NHR family has greatly expanded in nematodes; C. elegans has 284 NHRs, whereas humans have only 48. We show that the NHRs in the metabolic GRN have metabolic phenotypes, suggesting that they do not simply function redundantly.The mediator subunit MDT-15 preferentially interacts with NHRs that occur in the metabolic GRN.We describe an NHR circuit that responds to nutrient availability and propose a model for the evolution and organization of NHRs in C. elegans metabolic regulatory networks.
Physical and/or regulatory interactions between transcription factors (TFs) and their target genes are essential to establish body plans of multicellular organisms during development, and these interactions have been studied extensively in the context of GRNs. The precise control of differential gene expression is also of critical importance to maintain physiological homeostasis, and many metabolic disorders such as obesity and diabetes coincide with substantial changes in gene expression. Much work has focused on the GRNs that control metazoan development; however, the design principles and organization of the GRNs that control systems physiology remain largely unexplored.
In this study, we present the first gene-centered GRN that includes ∼70 genes involved in C. elegans metabolism and physiology, 100 TFs and more than 500 protein–DNA interactions between them. The resulting metabolic GRN is enriched for NHRs, compared with other gene-centered regulatory networks. NHRs are well-known regulators of lipid meta-qj;bolism in mammals. The transcriptional activity of NHRs can be modified by diffusible ligands, which allows these TFs to function as molecular sensors and rapidly alter the expression of their target genes. Interestingly, NHRs comprise the largest family of TFs in nematodes; the C. elegans genome encodes 284 NHRs, most of which are uncharacterized. Furthermore, their organization in GRNs has not yet been investigated. In our study, we show that the C. elegans NHRs that we retrieved in the metabolic GRN organize into network modules, and that most of these NHRs function to maintain lipid homeostasis in the nematode. Interestingly, network modularity has been proposed to facilitate rapid and robust changes in gene expression. Our results suggest that the C. elegans metabolic GRN may have evolved by combining NHR family expansion with the specific modular wiring of NHRs to enable the rapid adaptation of the animal to different environmental cues.
NHRs can interact with transcriptional cofactors such as chromatin remodeling complexes and Mediator components. For instance, the C. elegans Mediator subunit, MDT-15, can interact with NHR-49 to regulate the expression of its target genes. To find all the TFs that MDT-15 can interact with, we performed systematic yeast two-hybrid assays with MDT-15 versus 755 full-length TFs. We found that MDT-15 preferentially associates with NHRs, and specifically with those NHRs that confer a metabolic phenotype and that occur in the metabolic GRN. This illustrates the central role of MDT-15 in the regulation of metabolic gene expression.
Using a variety of genetic and biochemical approaches, we characterized NHR-86 in more detail. NHR-86 participates in one of the two NHR modules, and has a high-flux capacity; that is it has both a high incoming and a high outgoing degree. We obtained an nhr-86 mutant and generated an NHR-86 antibody, and showed that NHR-86 functions as an auto-repressor in vivo and that nhr-86 mutant animals store abnormally high levels of body fat.
Finally, we discovered a novel NHR circuit that responds to nutrient availability. In this circuit NHR-45 regulates the activity of nhr-178 promoter in two distinct physiologically important tissues: the intestine and the hypodermis. Both of these NHRs are required to maintain lipid homeostasis in C. elegans. The expression of nhr-178 is responsive to the nutritional status of the animal, which switches between ON and OFF states in the hypodermis. We found that NHR-45 activity is necessary to control this switch in the hypodermis. Interestingly, NHR-45 has opposite effects on the activity of the nhr-178 promoter in these tissues: NHR-45 activates this promoter in the intestine, but represses it in the hypodermis.
Altogether our study leads to a model in which the expansion of the NHR family, TFs that have the capacity to act as fast molecular sensors, is combined with a modular network organization to enable rapid and robust responses to various environmental cues.
Gene regulatory networks (GRNs) provide insights into the mechanisms of differential gene expression at a systems level. GRNs that relate to metazoan development have been studied extensively. However, little is still known about the design principles, organization and functionality of GRNs that control physiological processes such as metabolism, homeostasis and responses to environmental cues. In this study, we report the first experimentally mapped metazoan GRN of Caenorhabditis elegans metabolic genes. This network is enriched for nuclear hormone receptors (NHRs). The NHR family has greatly expanded in nematodes: humans have 48 NHRs, but C. elegans has 284, most of which are uncharacterized. We find that the C. elegans metabolic GRN is highly modular and that two GRN modules predominantly consist of NHRs. Network modularity has been proposed to facilitate a rapid response to different cues. As NHRs are metabolic sensors that are poised to respond to ligands, this suggests that C. elegans GRNs evolved to enable rapid and adaptive responses to different cues by a concurrence of NHR family expansion and modular GRN wiring.
PMCID: PMC2890327  PMID: 20461074
C. elegans; gene regulatory network; metabolism; nuclear hormone receptor; transcription factor
6.  The C. elegans Snail homolog CES-1 can activate gene expression in vivo and share targets with bHLH transcription factors 
Nucleic Acids Research  2009;37(11):3689-3698.
Snail-type transcription factors (TFs) are found in numerous metazoan organisms and function in a plethora of cellular and developmental processes including mesoderm and neuronal development, apoptosis and cancer. So far, Snail-type TFs are exclusively known as transcriptional repressors. They repress gene expression by recruiting transcriptional co-repressors and/or by preventing DNA binding of activators from the basic helix-loop-helix (bHLH) family of TFs to CAGGTG E-box sequences. Here we report that the Caenorhabditis elegans Snail-type TF CES-1 can activate transcription in vivo. Moreover, we provide results that suggest that CES-1 can share its binding site with bHLH TFs, in different tissues, rather than only occluding bHLH DNA binding. Together, our data indicate that there are at least two types of CES-1 target genes and, therefore, that the molecular function of Snail-type TFs is more plastic than previously appreciated.
PMCID: PMC2699517  PMID: 19372275

Results 1-6 (6)