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.

Chromatin remodeling system, cancer stem-like attractors, and cellular reprogramming

“…Using C. elegans, we and other researchers have demonstrated that NuRD-orchestrated anchor cell (AC) invasion programs could be relevant to metastasis [43,44]. These works would expand our understanding of the basis of metastasis.…”

Caenorhabditis elegans microRNAs of the let-7 family act in innate immune response circuits and confer robust developmental timing against pathogen stress

“…Therefore, the genetic programming of development includes mechanisms to ensure that developmental events occur flawlessly despite stressful conditions (1,2). Several studies indicate that microRNAs (miRNAs) are used to maintain the robustness of biological processes under stress conditions (3)(4)(5)(6)(7)(8)(9)(10). miRNAs are endogenous, noncoding, small RNAs that posttranscriptionally regulate gene expression primarily through binding to the 3′UTR of target mRNAs, which results in translation inhibition and/or mRNA degradation (11).…”

Gaps! Transgenesis, Model Organisms and Human Diseases

“…[14,15] [17,19,20] Likely lacking of adaptive immunity in C. elegans. Autoimmune diseases [3] Genetically modified food safety Difference in natural corn and non-natural corn.…”

“…On one hand, a gene product in a lower model organism might possibly have a larger function profile, possibly as a potential divergent function (2 or n)-in-1 homolog in mammalian systems; on the other hand, the tightly regulated gene expression and finely adjustable concentrations of physiological material in humans may exacerbate the difference by adding new complexity due to natural selection. However, many innovative methods of overcoming such gaps allow model organisms to contribute greatly to our knowledge of human health and the means of addressing human diseases [1][2][3][4]. We briefly review some recent studies and discuss some novel challenges to overcome.…”

“…However, we have been able to create an integrated transgenic DAF-12 worm with a few copies by means of DNA recombine ring and gene gun bombardment, which may replicate the natural regulatory settings, with no obvious compromise of the animal's natural functions. We conjecture that this transgenic organism may provide us with a potential counterbalance of DAF-12 protein prone to the degradation or un-stability during the harsh experimental process for a success of ChIP assays [3,7] and/or proteomics assays. Its endogenous protein cannot work well through the whole assay possibly due to its low abundance whatever.…”