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

Mei Yang; Ji Hoon Lee; Zhao Zhang; Richard De La Rosa; Mingjun Bi; Yuliang Tan; Yiji Liao; Juyeong Hong; Baowen Du; Yanming Wu; Jessica Scheirer; Tao Hong; Wei Li; Teng Fei; Chen-Lin Hsieh; Zhijie Liu; Wenbo Li; Michael G Rosenfeld; Kexin Xu

doi:10.1016/j.celrep.2020.107803

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.

Authors

Mei Yang¹, Ji Hoon Lee¹, Zhao Zhang¹, Richard De La Rosa¹, Mingjun Bi¹, Yuliang Tan², Yiji Liao¹, Juyeong Hong¹, Baowen Du¹, Yanming Wu¹, Jessica Scheirer¹, Tao Hong³, Wei Li⁴, Teng Fei⁵, Chen-Lin Hsieh⁶, Zhijie Liu¹, Wenbo Li⁷, Michael G Rosenfeld², Kexin Xu⁸

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].

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.

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding