title: DAF-12 regulates a connected network of genes to ensure robust developmental decisions.
abstract: 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.
authors.affiliation: Division of Geriatric Medicine, Department of Medicine, University of Pittsburgh, Pennsylvania, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hochbaum
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.forename: Carsten
authors.initials: C
authors.lastname: Stuckenholz
authors.forename: Paul
authors.initials: P
authors.lastname: Labhart
authors.forename: Vassili
authors.initials: V
authors.lastname: Alexiadis
authors.forename: René
authors.initials: R
authors.lastname: Martin
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Knölker
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Fisher
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; C410905:DAF-12 protein, C elegans; D035683:MicroRNAs; D018160:Receptors, Cytoplasmic and Nuclear