DAF-12 regulates a connected network of genes to ensure robust developmental decisions.
DAF-12 regulates a connected network of genes to ensure robust developmental decisions.
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DOI：
10.1371/journal.pgen.1002179
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发表时间：
2011-07
期刊：
影响因子：
4.5
通讯作者：
Fisher AL
中科院分区：
文献类型：
--
作者：
Hochbaum D;Zhang Y;Stuckenholz C;Labhart P;Alexiadis V;Martin R;Knölker HJ;Fisher AL
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. 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.
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影响因子：
11.8
作者：
Gerisch, B;Weitzel, C;Antebi, A
通讯作者：
Antebi, A
DOI：
10.1006/bbrc.2000.2260
发表时间：
2000-03-05
影响因子：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.0908131106
发表时间：
2009-11-03
影响因子：
11.1
作者：
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通讯作者：
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