Saravanan, B and Soota, D and Islam, Z and Majumdar, S and Mann, R and Meel, S and Farooq, U and Walavalkar, K and Gayen, S and Singh, AK and Hannenhalli, S and Notani, D (2020) Ligand dependent gene regulation by transient ERα clustered enhancers. In: PLoS Genetics, 16 (1).
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Abstract
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. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
| Item Type: | Journal Article |
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| Publication: | PLoS Genetics |
| Publisher: | Public Library of Science |
| Additional Information: | The copyright for this article belongs to the Authors. |
| Keywords: | estrogen receptor alpha; receptor interacting protein 140; trefoil factor 1; estrogen receptor alpha; histone; ligand; TFF1 protein, human; trefoil factor 1, Article; binding site; clustered regularly interspaced short palindromic repeat; controlled study; gene; gene cluster; gene control; gene deletion; gene expression; gene function; gene locus; gene targeting; human; human cell; ligand binding; NRIP1 gene; promoter region; protein binding; signal transduction; TFF1 gene; chromatin assembly and disassembly; enhancer region; genetics; MCF-7 cell line; metabolism, Chromatin Assembly and Disassembly; Enhancer Elements, Genetic; Estrogen Receptor alpha; Gene Deletion; Histones; Humans; Ligands; MCF-7 Cells; Trefoil Factor-1 |
| Department/Centre: | Division of Biological Sciences > Molecular Reproduction, Development & Genetics |
| Date Deposited: | 24 Jan 2023 04:57 |
| Last Modified: | 24 Jan 2023 04:57 |
| URI: | https://eprints.iisc.ac.in/id/eprint/79314 |
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