期刊
MOLECULAR CELL
卷 71, 期 4, 页码 526-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2018.07.039
关键词
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资金
- Cancer Research Institute Irvington Postdoctoral Fellowship
- American Cancer Society Postdoctoral Fellowship [PF-16-211-01-TBE]
- NIH [DK018477, DK039949, NS034934, CA173903]
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 (ER alpha)-dependent transcriptional repression program. The unexpected signature for this E-2-induced program resides in indirect recruitment of ER alpha to a large cohort of pioneer factor basally active FOXA1-bound enhancers that lack cognate ER alpha DNA-binding elements. Surprisingly, these basally active estrogen-repressed (BAER) enhancers are decommissioned by ER alpha-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.
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