DAF-12 Regulates a Connected Network of Genes to Ensure Robust Developmental Decisions
| Autor: | Paul Labhart, Alfred L. Fisher, Daniel Hochbaum, Hans-Joachim Knölker, Yue Zhang, Vassili Alexiadis, René Martin, Carsten Stuckenholz |
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| Rok vydání: | 2011 |
| Předmět: |
Chromatin Immunoprecipitation
Cancer Research lcsh:QH426-470 Gene regulatory network Receptors Cytoplasmic and Nuclear Biology Animals Genetically Modified 03 medical and health sciences 0302 clinical medicine Genetics Animals Humans Gene Regulatory Networks Caenorhabditis elegans Caenorhabditis elegans Proteins Molecular Biology Gene Genetics (clinical) Ecology Evolution Behavior and Systematics 030304 developmental biology Regulation of gene expression 0303 health sciences Binding Sites Tiling array Base Sequence fungi Gene Expression Regulation Developmental Genomics biology.organism_classification Phenotype lcsh:Genetics MicroRNAs HEK293 Cells Mutation Chromatin immunoprecipitation Heterochrony 030217 neurology & neurosurgery Research Article Developmental Biology |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 7, Iss 7, p e1002179 (2011) |
| ISSN: | 1553-7404 |
| Popis: | The nuclear receptor DAF-12 has roles in normal development, the decision to pursue dauer development in unfavorable conditions, and the modulation of adult aging. Despite the biologic importance of DAF-12, target genes for this receptor are largely unknown. To identify DAF-12 targets, we performed chromatin immunoprecipitation followed by hybridization to whole-genome tiling arrays. We identified 1,175 genomic regions to be bound in vivo by DAF-12, and these regions are enriched in known DAF-12 binding motifs and act as DAF-12 response elements in transfected cells and in transgenic worms. The DAF-12 target genes near these binding sites include an extensive network of interconnected heterochronic and microRNA genes. We also identify the genes encoding components of the miRISC, which is required for the control of target genes by microRNA, as a target of DAF-12 regulation. During reproductive development, many of these target genes are misregulated in daf-12(0) mutants, but this only infrequently results in developmental phenotypes. In contrast, we and others have found that null daf-12 mutations enhance the phenotypes of many miRISC and heterochronic target genes. We also find that environmental fluctuations significantly strengthen the weak heterochronic phenotypes of null daf-12 alleles. During diapause, DAF-12 represses the expression of many heterochronic and miRISC target genes, and prior work has demonstrated that dauer formation can suppress the heterochronic phenotypes of many of these target genes in post-dauer development. Together these data are consistent with daf-12 acting to ensure developmental robustness by committing the animal to adult or dauer developmental programs despite variable internal or external conditions. Author Summary In Caenorhabditis elegans many life history decisions, such as interrupting reproductive development to form a dauer and the rate of aging, are under the control of the DAF-12 nuclear receptor. Recent work has started to elucidate the endocrine regulation of DAF-12, but few target genes for this receptor have been identified. In this study, we use chromatin immunoprecipitation to identify in vivo target genes for DAF-12. Among the targets are multiple genes involved in developmental progression, which are termed heterochronic genes, and subunits of the miRISC, which is required for the control of target genes by microRNA. In daf-12 null worms, both heterochronic and miRISC genes are mis-regulated, but development is usually normal. This led us to examine whether DAF-12 normally acts to reinforce commitment to dauer or adult development and prevent disruption by environmental or genetic fluctuations. Consistent with this, we find that daf-12 mutants are hypersensitive to environmental fluctuations and mutations in individual target genes. These results suggest a novel role for daf-12 as a phenotypic capacitor that ensures commitment to reproductive or dauer development despite internal and external variations. |
| Databáze: | OpenAIRE |
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