1. Dismissal of RNA Polymerase II Underlies a Large Ligand-Induced Enhancer Decommissioning Program
- Author
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Tan, Yuliang, Jin, Chunyu, Ma, Wubin, Hu, Yiren, Tanasa, Bogdan, Oh, Soohwan, Gamliel, Amir, Ma, Qi, Yao, Lu, Zhang, Jie, Ohgi, Kenny, Liu, Wen, Aggarwal, Aneel K, and Rosenfeld, Michael G
- Subjects
Genetics ,Biotechnology ,Base Sequence ,Binding Sites ,CRISPR-Cas Systems ,Enhancer Elements ,Genetic ,Estradiol ,Estrogen Receptor alpha ,F-Box Proteins ,Gene Editing ,Gene Expression Regulation ,HEK293 Cells ,Hepatocyte Nuclear Factor 3-alpha ,Histones ,Humans ,Jumonji Domain-Containing Histone Demethylases ,MCF-7 Cells ,Nedd4 Ubiquitin Protein Ligases ,Protein Binding ,RNA ,RNA Polymerase II ,Signal Transduction ,Transcription ,Genetic ,Ubiquitination ,ERα ,KDM2A ,NEDD4 ,Pol II ,decommission ,eRNA ,enhancer ,nuclear receptor ,repression ,transcription ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - 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 E2-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.
- Published
- 2018