DAF-12 regulates a connected network of genes to ensure robust developmental decisions.

DANIEL HOCHBAUM; ALFRED L. FISHER

Encuentro; Research day on Aging; 2011

The nuclear receptor DAF-12 has roles in normal development, in the decision to pursue dauer development in unfavorable conditions, and in the modulation of adult aging. Despite the 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 1175 genomic regions as being 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 genes near these binding sites include an extensive network of interconnected heterochronic and microRNA genes as DAF-12 targets. We also identified the genes of the miRISC complex, which are required for the control of target genes by microRNA, as putative DAF-12 target genes. During reproductive development, null alleles of daf-12 produce mis-regulation of many of these genes, but only infrequently result 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 found that environmental fluctuations significantly strengthen the weak heterochronic phenotypes of null daf-12 alleles. Further in diapause, DAF-12 represses the heterochronic and miRISC target genes, and prior work demonstrates that dauer formation can often suppress the heterochronic phenotypes for many of these target genes in post dauer development. Together these data are consistent with daf-12 acting to ensure developmental robustness to ensure commitment to adult or dauer developmental programs despite variable internal or external conditions.