Enhancer RNAs Mediate Estrogen-Induced Decommissioning of Selective Enhancers by Recruiting ERα and Its Cofactor

Cell Rep. 2020 Jun 23;31(12):107803. doi: 10.1016/j.celrep.2020.107803.


The function of enhancer RNAs (eRNAs) in transcriptional regulation remains obscure. By analyzing the genome-wide nascent transcript profiles in breast cancer cells, we identify a special group of eRNAs that are essential for estrogen-induced transcriptional repression. Using eRNAs of TM4SF1 and EFEMP1 as the paradigms, we find that these RNA molecules not only stabilize promoter-enhancer interactions but also recruit liganded estrogen receptor α (ERα) to particular enhancer regions, facilitate the formation of a functional transcriptional complex, and cause gene silencing. Interestingly, ERα is shown to directly bind with eRNAs by its DNA-binding domain. These eRNAs help with the formation of a specific ERα-centered transcriptional complex and promote the association of the histone demethylase KDM2A, which dismisses RNA polymerase II from designated enhancers and suppresses the transcription of target genes. Our work demonstrates a complete mechanism underlying the action of eRNAs in modulating and refining the locus-specific transcriptional program.

Keywords: ERα signaling; enhancer RNA; enhancer activity regulation; transcriptional repression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Down-Regulation / genetics
  • Enhancer Elements, Genetic*
  • Estrogen Receptor alpha / chemistry
  • Estrogen Receptor alpha / metabolism*
  • Estrogens / metabolism*
  • F-Box Proteins / metabolism
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Models, Biological
  • Open Reading Frames / genetics
  • Protein Binding
  • Protein Domains
  • RNA / metabolism*
  • RNA Polymerase II / metabolism
  • Transcription, Genetic


  • Estrogen Receptor alpha
  • Estrogens
  • F-Box Proteins
  • RNA
  • Jumonji Domain-Containing Histone Demethylases
  • KDM2A protein, human
  • RNA Polymerase II