Genome-wide endogenous DAF-16/FOXO recruitment dynamics during lowered insulin signalling in C. elegans.
Genome-wide endogenous DAF-16/FOXO recruitment dynamics during lowered insulin signalling in C. elegans.
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DOI：
10.18632/oncotarget.6282
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发表时间：
2015-12-08
期刊：
影响因子：
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通讯作者：
Mukhopadhyay A
中科院分区：
文献类型：
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作者：
Kumar N;Jain V;Singh A;Jagtap U;Verma S;Mukhopadhyay A
降低胰岛素-IGF-1样信号（IIS）激活FOXO转录因子（TF），以延长物种的寿命。研究在此条件下，C.在elegans中，我们报告了内源性β-16的第一个募集概况，并表明该反应是保守的。β-16主要作为转录激活因子，并且在0.5 kb启动子近端区域内的结合导致对编码参与解毒和长寿的蛋白质的下游靶标的最大诱导。有趣的是，在低IIS下激活的基因在WT中已经有较高的α-16募集到其启动子中。在低IIS期间，foxo-16结合于基因的启动子近端区域中的FOXO共有序列的变体，所述基因是专门靶向的。在比较多项研究后，我们还定义了一组“核心”直接靶点，这些靶点倾向于共表达并对IIS相关表型做出强有力的贡献。此外，我们表明，核激素受体E12以及锌指TF EOR-1可以结合DNA在接近E16和不同的TF类，是E16的直接目标可能有助于调节其间接目标。总之，我们的研究提供了对FOXO/foxo-16的转录生物学和IIS途径下游基因调控的基本见解。
Lowering insulin-IGF-1-like signalling (IIS) activates FOXO transcription factors (TF) to extend life span across species. To study the dynamics of FOXO chromatin occupancy under this condition in C. elegans, we report the first recruitment profile of endogenous DAF-16 and show that the response is conserved. DAF-16 predominantly acts as a transcriptional activator and binding within the 0.5 kb promoter-proximal region results in maximum induction of downstream targets that code for proteins involved in detoxification and longevity. Interestingly, genes that are activated under low IIS already have higher DAF-16 recruited to their promoters in WT. DAF-16 binds to variants of the FOXO consensus sequence in the promoter proximal regions of genes that are exclusively targeted during low IIS. We also define a set of ‘core’ direct targets, after comparing multiple studies, which tend to co-express and contribute robustly towards IIS-associated phenotypes. Additionally, we show that nuclear hormone receptor DAF-12 as well as zinc-finger TF EOR-1 may bind DNA in close proximity to DAF-16 and distinct TF classes that are direct targets of DAF-16 may be instrumental in regulating its indirect targets. Together, our study provides fundamental insights into the transcriptional biology of FOXO/DAF-16 and gene regulation downstream of the IIS pathway.