Author:
Murakami Shino,Nagari Anusha,Kraus W. Lee
Abstract
Although many features of active transcriptional enhancers have been defined by genomic assays, we lack a clear understanding of the order of events leading to enhancer formation and activation as well as the dynamics of coregulator interactions within the enhancer complex. Here, we used selective loss- or gain-of-function mutants of estrogen receptor α (ERα) to define two distinct phases of ligand-dependent enhancer formation. In the first phase (0–20 min), p300 is recruited to ERα by Mediator as well as p300's acetylhistone-binding bromodomain to promote initial enhancer formation, which is not competent for sustained activation. In the second phase (20–45 min), p300 is recruited to ERα by steroid receptor coregulators (SRCs) for enhancer maturation and maintenance. Successful transition between these two phases (“coregulator switching”) is required for proper enhancer function. Failure to recruit p300 during either phase leads to abortive enhancer formation and a lack of target gene expression. Our results reveal an ordered and cooperative assembly of ERα enhancers requiring functional interplay among p300, Mediator, and SRCs, which has implications for hormone-dependent gene regulation in breast cancers. More broadly, our results demonstrate the unexpectedly dynamic nature of coregulator interactions within enhancer complexes, which are likely to be a defining feature of all enhancers.
Funder
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases
Cancer Prevention and Research Institute of Texas
Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
54 articles.
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