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首页> 外文期刊>PLoS Genetics >Ligand dependent gene regulation by transient ERα clustered enhancers
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Ligand dependent gene regulation by transient ERα clustered enhancers

机译：通过瞬时ERα聚簇增强剂的配体依赖性基因调节

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Unliganded Estrogen receptor alpha (ERα) has been implicated in ligand-dependent gene regulation. Upon ligand exposure, ERα binds to several EREs relatively proximal to the pre-marked, unliganded ERα-bound sites and affects transient but robust gene expression. However, the underlying mechanisms are not fully understood. Here we demonstrate that upon ligand stimulation, persistent sites interact extensively, via chromatin looping, with the proximal transiently ERα-bound sites, forming Ligand Dependent ERα Enhancer Cluster in 3D (LDEC). The E2-target genes are regulated by these clustered enhancers but not by the H3K27Ac super-enhancers. Further, CRISPR-based deletion of TFF1 persistent site disrupts the formation of its LDEC resulting in the loss of E2-dependent expression of TFF1 and its neighboring genes within the same TAD. The LDEC overlap with nuclear ERα condensates that coalesce in a ligand and persistent site dependent manner. Furthermore, formation of clustered enhancers, as well as condensates, coincide with the active phase of signaling and their later disappearance results in the loss of gene expression even though persistent sites remain bound by ERα. Our results establish, at TFF1 and NRIP1 locus, a direct link between ERα condensates, ERα enhancer clusters, and transient, but robust, gene expression in a ligand-dependent fashion.
机译：被解密的雌激素受体α（ERα）已涉及配体依赖性基因调控。在配体曝光时，ERα与预标记的预析ERα结合位点相对近似的几个ERE结合，并影响瞬时但稳健的基因表达。但是，潜在机制尚未完全理解。在这里，我们证明，在配体刺激时，持久性位点通过染色质环化与近端瞬时ERα结合的位点相互作用，形成3D（LDEC）的配体依赖性ERα增强子簇。 E2-靶基因由这些聚类增强子调节，但不是H3K27AC超强子。此外，基于CRFR的删除TFF1持久性网站扰乱了其LDEC的形成，从而导致TFF1和其相邻基因的E2依赖表达的丧失。 LDEC与核ERα的缩合物重叠，该冷凝物在配体和持续的位点依赖性的方式下聚结。此外，组分增强剂的形成以及缩合物与信号传导的活性相一致，并且它们后来的消失导致基因表达的丧失，即使持久性位点仍然被ERα留下。我们的结果在TFF1和NRIP1基因座中建立了ERα缩合物，ERα增强剂簇之间的直接链接，血管依赖性时尚的凝结，ERα增强剂簇和瞬态，但鲁棒，基因表达。

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