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

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.