Enhancer RNAs Mediate Estrogen-Induced Decommissioning of Selective Enhancers by Recruiting Erα and Its Cofactor
58 Pages Posted: 6 Dec 2019 Sneak Peek Status: Under ReviewMore...
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.
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