Chromatin accessibility pre-determines glucocorticoid receptor binding patterns.
Chromatin accessibility pre-determines glucocorticoid receptor binding patterns.
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DOI：
10.1038/ng.759
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发表时间：
2011-03
期刊：
影响因子：
30.8
通讯作者：
Stamatoyannopoulos JA
中科院分区：
文献类型：
--
作者：
John S;Sabo PJ;Thurman RE;Sung MH;Biddie SC;Johnson TA;Hager GL;Stamatoyannopoulos JA
发育、分化以及对环境刺激的反应，其特征是受调控的转录因子与它们的同源基因组位点从头结合所引发的细胞状态的连续变化。一个给定的调控因子从无数潜在的基因组结合位点中选择有限数量的体内靶标的机制尚未确定。在此我们表明，糖皮质激素受体（一种典型的配体激活转录因子）多达95%的诱导性从头基因组结合靶向于预先存在的可接近染色质焦点。因子结合总是增强染色质的可接近性。细胞选择性的糖皮质激素受体基因组占据模式似乎完全由基线染色质可接近性模式中的细胞特异性差异预先决定，局部序列特征也有次要贡献。这些结果为理解调控因子 - 基因组相互作用定义了一个新的框架，并为类固醇药物以及其他与活基因组相互作用的药物的组织选择性提供了分子基础。
Development, differentiation, and response to environmental stimuli are characterized by sequential changes in cellular state initiated by the de novo binding of regulated transcriptional factors to their cognate genomic sites. The mechanism whereby a given regulatory factor selects a limited number of in vivo targets from myriads of potential genomic binding sites is undetermined. Here we show that up to 95% of induced de novo genomic binding by the glucocorticoid receptor, a paradigmatic ligand-activated transcription factor, is targeted to pre-existing foci of accessible chromatin. Factor binding invariably potentiates chromatin accessibility. Cell-selective glucocortocoid receptor genomic occupancy patterns appear to be comprehensively pre-determined by cell-specific differences in baseline chromatin accessibility patterns, with secondary contributions from local sequence features. The results define a novel framework for understanding regulatory factor-genome interactions, and provide a molecular basis for the tissue-selectivity of steroid pharmaceuticals and other agents that intersect the living genome.
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