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.
Mei Yang  1 ,  Ji Hoon Lee  1 ,  Zhao Zhang  1 ,  Richard De La Rosa  1 ,  Mingjun Bi  1 ,  Yuliang Tan  2 ,  Yiji Liao  1 ,  Juyeong Hong  1 ,  Baowen Du  1 ,  Yanming Wu  1 ,  Jessica Scheirer  1 ,  Tao Hong  3 ,  Wei Li  4 ,  Teng Fei  5 ,  Chen-Lin Hsieh  6 ,  Zhijie Liu  1 ,  Wenbo Li  7 ,  Michael G Rosenfeld  2 ,  Kexin Xu  8
Affiliations
  • 1. Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  • 2. Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, CA 92093, USA.
  • 3. Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Xiangya School of Medicine, Central South University, Changsha 410008, China.
  • 4. Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA; Division of Biostatistics, Dan L. Duncan Comprehensive Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5. College of Life and Health Sciences, Northeastern University, Shenyang 110819, China.
  • 6. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 7. Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center and UTHealth, Houston, TX 77030, USA.
  • 8. Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. Electronic address: [email protected].
PMID: 32579929 DOI: 10.1016/j.celrep.2020.107803
Abstract

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.
Products