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

58 Pages Posted: 6 Dec 2019 Sneak Peek Status: Review Complete

See all articles by Mei Yang

Mei Yang

University of Texas at San Antonio - Department of Molecular Medicine

Ji-Hoon Lee

University of Texas at San Antonio - Department of Molecular Medicine

Zhao Zhang

University of Texas at San Antonio - Department of Molecular Medicine

Mingjun Bi

University of Texas at San Antonio - Department of Molecular Medicine

Yuliang Tan

University of California, San Diego (UCSD), Health Sciences, Howard Hughes Medical Institute

Yiji Liao

University of Texas at San Antonio - Department of Molecular Medicine

Juyeong Hong

University of Texas at San Antonio - Department of Molecular Medicine

Baowen Du

University of Texas at San Antonio - Department of Molecular Medicine

Yanming Wu

University of Texas at San Antonio - Department of Molecular Medicine

Richard De La Rosa

University of Texas at San Antonio - Department of Molecular Medicine

Tao Hong

University of Texas at San Antonio - Department of Molecular Medicine

Wei Li

University of California, Irvine - Department of Biological Chemistry

Teng Fei

Northeastern University, China - College of Life and Health Sciences

Chen-Lin Hsieh

Dana-Farber/Harvard Cancer Center - Center for Functional Cancer Epigenetics

Zhijie Liu

University of Texas at San Antonio - Department of Molecular Medicine

Wenbo Li

University of Texas at Houston - Department of Biochemistry and Molecular Biology

Michael G. Rosenfeld

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine

Kexin Xu

University of Texas at San Antonio - Department of Molecular Medicine

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Abstract

Although accumulating evidence has demonstrated that individual enhancer RNAs (eRNAs) exert critical biological functions rather than being passive transcriptional byproducts, the mechanisms of action of these non-coding transcripts remain obscure and divergent. By analyzing genome-wide nascent transcript profiling in breast cancer cells, we identified a special group of eRNAs that are functionally important for estrogen-induced transcriptional repression. Using eRNAs of TM4SF1 and EFEMP1 as the paradigms, we found that these RNA molecules not only stabilize promoter-enhancer looping structure, but also recruit liganded estrogen receptor α (ERα) to particular enhancers of target genes, facilitate the hierarchical formation of a functional transcriptional complex, and cause gene downregulation. Interestingly, we found that ERα directly binds to eRNAs via its DNA-binding domain. These eRNAs help with the formation of a specific ERa-centered transcriptional complex and promote the association of the histone demethylase KDM2A, which dismisses RNA polymerase II from designated enhancers and suppresses transcription of target genes. Our work demonstrated a complete mechanism underlying the function of eRNAs, as a distinctive class of cis-acting RNA molecules, in modulating and refining locus-specific transcriptional program.

Keywords: enhancer RNA, transcriptional repression, ERa signaling, enhancer activity regulation.

Suggested Citation

Yang, Mei and Lee, Ji-Hoon and Zhang, Zhao and Bi, Mingjun and Tan, Yuliang and Liao, Yiji and Hong, Juyeong and Du, Baowen and Wu, Yanming and De La Rosa, Richard and Hong, Tao and Li, Wei and Fei, Teng and Hsieh, Chen-Lin and Liu, Zhijie and Li, Wenbo and Rosenfeld, Michael G. and Xu, Kexin, Enhancer RNAs Mediate Estrogen-Induced Decommissioning of Selective Enhancers by Recruiting Erα and Its Cofactor (December 3, 2019). Available at SSRN: https://ssrn.com/abstract=3497740 or http://dx.doi.org/10.2139/ssrn.3497740
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Mei Yang

University of Texas at San Antonio - Department of Molecular Medicine

San Antonio, TX
United States

Ji-Hoon Lee

University of Texas at San Antonio - Department of Molecular Medicine

San Antonio, TX
United States

Zhao Zhang

University of Texas at San Antonio - Department of Molecular Medicine

San Antonio, TX
United States

Mingjun Bi

University of Texas at San Antonio - Department of Molecular Medicine

San Antonio, TX
United States

Yuliang Tan

University of California, San Diego (UCSD), Health Sciences, Howard Hughes Medical Institute

9500 Gilman Drive
La Jolla, CA
United States

Yiji Liao

University of Texas at San Antonio - Department of Molecular Medicine

San Antonio, TX
United States

Juyeong Hong

University of Texas at San Antonio - Department of Molecular Medicine

San Antonio, TX
United States

Baowen Du

University of Texas at San Antonio - Department of Molecular Medicine

San Antonio, TX
United States

Yanming Wu

University of Texas at San Antonio - Department of Molecular Medicine

San Antonio, TX
United States

Richard De La Rosa

University of Texas at San Antonio - Department of Molecular Medicine

San Antonio, TX
United States

Tao Hong

University of Texas at San Antonio - Department of Molecular Medicine

San Antonio, TX
United States

Wei Li

University of California, Irvine - Department of Biological Chemistry

Irvine, CA 92697
United States

Teng Fei

Northeastern University, China - College of Life and Health Sciences

195 Chuangxin Rd
Life Sciences Building A426
Shenyang, 110169
China

Chen-Lin Hsieh

Dana-Farber/Harvard Cancer Center - Center for Functional Cancer Epigenetics

450 Brookline Avenue
Boston, MA 02115
United States

Zhijie Liu

University of Texas at San Antonio - Department of Molecular Medicine

San Antonio, TX
United States

Wenbo Li

University of Texas at Houston - Department of Biochemistry and Molecular Biology

Houston, TX
United States

Michael G. Rosenfeld

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine ( email )

La Jolla, CA
United States

Kexin Xu (Contact Author)

University of Texas at San Antonio - Department of Molecular Medicine ( email )

San Antonio, TX
United States

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