Pre-established Chromatin Interactions Mediate the Genomic Response to Glucocorticoids
Pre-established Chromatin Interactions Mediate the Genomic Response to Glucocorticoids
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DOI：
10.1016/j.cels.2018.06.007
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发表时间：
2018-08-22
期刊：
影响因子：
9.3
通讯作者：
Reddy, Timothy E.
中科院分区：
文献类型：
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作者：
D'lppolito, Anthony M.;McDowell, Ian C.;Reddy, Timothy E.
糖皮质激素受体（GR）是一种参与代谢和抗炎基因表达反应的糖皮质激素诱导型转录因子。为了研究是什么控制GR结合位点与其靶基因之间的相互作用，我们使用原位Hi-C生成糖皮质激素治疗前后染色质相互作用的高分辨率全基因组图谱。我们发现GR与基因组的结合通常不会引起新的染色质与靶基因的相互作用，而是通过激素治疗前已经存在的染色质相互作用起作用。糖皮质激素诱导和糖皮质激素抑制基因增加与远端GR结合位点的相互作用。此外，虽然糖皮质激素诱导的基因增加了与转录活性染色体区室的相互作用，糖皮质激素抑制的基因增加了与转录沉默区室的相互作用。最后，虽然建筑DNA结合蛋白CTCF和RAD 21被绑定到大多数染色质相互作用，我们发现，糖皮质激素响应染色质相互作用耗尽CTCF结合，但富集RAD 21。总之，这些发现为GC介导的基因激活和抑制的机制提供了新的见解。
The glucocorticoid receptor (GR) is a hormone-inducible transcription factor involved in metabolic and anti-inflammatory gene expression responses. To investigate what controls interactions between GR binding sites and their target genes, we used in situ Hi-C to generate high-resolution, genome-wide maps of chromatin interactions before and after glucocorticoid treatment. We found that GR binding to the genome typically does not cause new chromatin interactions to target genes but instead acts through chromatin interactions that already exist prior to hormone treatment. Both glucocorticoid-induced and glucocorticoid-repressed genes increased interactions with distal GR binding sites. In addition, while gluco-corticoid-induced genes increased interactions with transcriptionally active chromosome compartments, glucocorticoid-repressed genes increased interactions with transcriptionally silent compartments. Lastly, while the architectural DNA-binding proteins CTCF and RAD21 were bound to most chromatin interactions, we found that glucocorticoid-responsive chromatin interactions were depleted for CTCF binding but enriched for RAD21. Together, these findings offer new insights into the mechanisms underlying GC-mediated gene activation and repression.