Ligand dependent gene regulation by transient ER? clustered enhancers.

ABSTRACT: Unliganded Estrogen receptor alpha (ER?) has been implicated in ligand-dependent gene regulation. Upon ligand exposure, ER? binds to several EREs relatively proximal to the pre-marked, unliganded ER?-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 ER?-bound sites, forming Ligand Dependent ER? 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 ER? 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 ER?. Our results establish, at TFF1 and NRIP1 locus, a direct link between ER? condensates, ER? enhancer clusters, and transient, but robust, gene expression in a ligand-dependent fashion.

SUBMITTER: Saravanan B 

PROVIDER: S-EPMC6975561 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature