Divergent Transcription of the Locus Generates Two Enhancer RNAs with Opposing Functions.

Enhancer RNAs (eRNAs) are a subset of long noncoding RNA generated from genomic enhancers: they are thought to act as potent promoters of the expression of nearby genes through interaction with the transcriptional and epigenomic machineries. In the present work, we describe two eRNAs transcribed from the enhancer of a gene specifying a master cardiomyogenic lineage transcription factor (TF)-which we call Intergenic Regulatory Element Nkx2-5 Enhancers (s). The s are encoded, respectively, on the same strand (SS) and in the divergent direction (div) respect to the nearby gene. Of note, these two eRNAs have opposing roles in the regulation of : acts as a canonical promoter of transcription, whereas represses the activity of the enhancer through recruitment of the histone deacetylase sirtuin 1. Thus, we have identified an autoregulatory loop controlling expression of the master cardiac TF NKX2-5, in which one eRNA represses transcription.