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

Molecular cell | 2018

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.

Pubmed ID: 30118678 RIS Download

Associated grants

  • Agency: NINDS NIH HHS, United States
    Id: R01 NS034934
  • Agency: NIDDK NIH HHS, United States
    Id: R37 DK039949
  • Agency: NCI NIH HHS, United States
    Id: R01 CA213371
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK018477
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK039949
  • Agency: Howard Hughes Medical Institute, United States
  • Agency: NIDDK NIH HHS, United States
    Id: T32 DK007044
  • Agency: NCI NIH HHS, United States
    Id: R01 CA173903

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This is a list of tools and resources that we have found mentioned in this publication.


SAM format (tool)

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FBXL11 antibody (antibody)

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SAMTOOLS (software resource)

RRID:SCR_002105

Original SAMTOOLS package has been split into three separate repositories including Samtools, BCFtools and HTSlib. Samtools for manipulating next generation sequencing data used for reading, writing, editing, indexing,viewing nucleotide alignments in SAM,BAM,CRAM format. BCFtools used for reading, writing BCF2,VCF, gVCF files and calling, filtering, summarising SNP and short indel sequence variants. HTSlib used for reading, writing high throughput sequencing data.

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Bowtie 2 (software resource)

RRID:SCR_016368

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MCF-7 (cell line)

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