Dismissal of RNA Polymerase II Underlies a Large Ligand-Induced Enhancer Decommissioning Program

Yuliang Tan, Chunyu Jin, Wubin Ma, Yiren Hu, Bogdan Tanasa, Soohwan Oh, Amir Gamliel, Qi Ma, Lu Yao, Jie Zhang, Kenny Ohgi, Wen Liu, Aneel K. Aggarwal, Michael G. Rosenfeld

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Nuclear receptors induce both transcriptional activation and repression programs responsible for development, homeostasis, and disease. Here, we report a previously overlooked enhancer decommissioning strategy underlying a large estrogen receptor alpha (ERα)-dependent transcriptional repression program. The unexpected signature for this E 2 -induced program resides in indirect recruitment of ERα to a large cohort of pioneer factor basally active FOXA1-bound enhancers that lack cognate ERα DNA-binding elements. Surprisingly, these basally active estrogen-repressed (BAER) enhancers are decommissioned by ERα-dependent recruitment of the histone demethylase KDM2A, functioning independently of its demethylase activity. Rather, KDM2A tethers the E3 ubiquitin-protein ligase NEDD4 to ubiquitylate/dismiss Pol II to abrogate eRNA transcription, with consequent target gene downregulation. Thus, our data reveal that Pol II ubiquitylation/dismissal may serve as a potentially broad strategy utilized by indirectly bound nuclear receptors to abrogate large programs of pioneer factor-mediated, eRNA-producing enhancers. Tan et al. discover a mechanism underlying repression of a large basally active estrogen-repressed (BAER) enhancer program. The expression of these basally active genes in human breast cancer cells is repressed by estrogen, and the indirectly bound ERα (in trans) at BAER enhancers dismisses RNA Pol II to abrogate large, eRNA-producing enhancer programs.

Original languageEnglish
Pages (from-to)526-539.e8
JournalMolecular Cell
Volume71
Issue number4
DOIs
StatePublished - 16 Aug 2018

Keywords

  • ERα
  • KDM2A
  • NEDD4
  • Pol II
  • decommission
  • eRNA
  • enhancer
  • nuclear receptor
  • repression
  • transcription

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