Enhancer RNAs mediate estrogen-induced decommissioning of selective enhancers by recruiting ERa and its cofactor
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 a (ERa) to particular enhancer regions, facilitate the formation of a functional transcriptional complex, and cause gene silencing. Interestingly, ERa is shown to directly bind with 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 the transcription of target genes. Our work demonstrates a complete mechanism underlying the action of eRNAs in modulating and refining locus-specific transcriptional program.
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, and Kexin Xu