Ligand dependent gene regulation by transient ERα clustered enhancers


Autoři: Bharath Saravanan aff001;  Deepanshu Soota aff001;  Zubairul Islam aff001;  Sudeshna Majumdar aff003;  Rajat Mann aff001;  Sweety Meel aff001;  Umer Farooq aff001;  Kaivalya Walavalkar aff001;  Srimonta Gayen aff003;  Anurag Kumar Singh aff001;  Sridhar Hannenhalli aff005;  Dimple Notani aff001
Působiště autorů: Genetics and Development, National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India aff001;  School of Chemical & Biotechnology, SASTRA Deemed University, Thanjavur, Tamil Nadu, India aff002;  Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India aff003;  Centre for Functional Genomics and Bio-informatics, The University of Trans-Disciplinary Health Sciences and Technology, Bangalore, India aff004;  Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, United States of America aff005
Vyšlo v časopise: Ligand dependent gene regulation by transient ERα clustered enhancers. PLoS Genet 16(1): e32767. doi:10.1371/journal.pgen.1008516
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008516

Souhrn

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, or persistent, 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.

Klíčová slova:

Cell binding – Gene expression – Gene regulation – Genomic libraries – Genomic signal processing – Guide RNA – Chromatin – ChIA PET


Zdroje

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