Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation

It is unclear whether bidirectional non-coding RNAs transcribed from enhancer elements (eRNAs) have any functional role; here, eRNA transcription is shown to be functionally important during the activation of genes by the oestrogen receptor in human breast cancer cells. Regulatory role for eRNAs Bidirectional non-coding RNAs are transcribed from enhancer elements, but it is unclear whether these enhancer-derived RNAs (eRNAs) have a functional role or are merely a reflection of enhancer activity. Two manuscripts in this issue of Nature examine this question in the context of the positive and negative transcriptional functions of different nuclear receptors. Wenbo Li et al . provide evidence for the functional importance of eRNA transcription during the activation of genes by the oestrogen receptor in breast cancer cell lines; and Michael Lam et al . show that the repressive functions of Rev-Erb nuclear receptors in macrophages are linked to their ability to inhibit the transcription of eRNAs. Taken together these studies provide evidence for a role for eRNAs in contributing to enhancer functions. The functional importance of gene enhancers in regulated gene expression is well established 1 , 2 , 3 . In addition to widespread transcription of long non-coding RNAs (lncRNAs) in mammalian cells 4 , 5 , 6 , bidirectional ncRNAs are transcribed on enhancers, and are thus referred to as enhancer RNAs (eRNAs) 7 , 8 , 9 . However, it has remained unclear whether these eRNAs are functional or merely a reflection of enhancer activation. Here we report that in human breast cancer cells 17β-oestradiol (E2)-bound oestrogen receptor α (ER-α) causes a global increase in eRNA transcription on enhancers adjacent to E2-upregulated coding genes. These induced eRNAs, as functional transcripts, seem to exert important roles for the observed ligand-dependent induction of target coding genes, increasing the strength of specific enhancer–promoter looping initiated by ER-α binding. Cohesin, present on many ER-α-regulated enhancers even before ligand treatment, apparently contributes to E2-dependent gene activation, at least in part by stabilizing E2/ER-α/eRNA-induced enhancer–promoter looping. Our data indicate that eRNAs are likely to have important functions in many regulated programs of gene transcription.