Enhancer RNA Facilitates NELF Release from Immediate Early Genes

Enhancer RNAs (eRNAs) are a class of long noncoding RNAs (lncRNA) expressed from active enhancers, whose function and action mechanism are yet to be firmly established. Here we show that eRNAs facilitate the transition of paused RNA polymerase II (RNAPII) into productive elongation by acting as a decoy for the negative elongation factor (NELF) complex upon induction of immediate early genes (IEGs) in neurons. eRNAs are synthesized prior to the culmination of target gene transcription and interact with the NELF complex. Knockdown of eRNAs expressed at neuronal enhancers impairs transient release of NELF from the specific target promoters during transcriptional activation, coinciding with a decrease in target mRNA induction. The enhancer-promoter interaction was unaffected by eRNA knockdown. Instead, chromatin looping might enable eRNAs to act locally at a specific promoter. Our findings highlight the spatiotemporally regulated action mechanism of eRNAs during early transcriptional elongation. [Display omitted] •eRNAs play a modulatory role in the expression of neuronal immediate early genes•eRNAs facilitate NELF release from the target promoter•The interaction between NELF-E and eRNAs is dependent on the RRM domain•The activity-induced enhancer-promoter interaction does not require eRNAs Transcription from enhancers produces eRNAs, but how eRNAs influence gene activation is unclear. Schaukowitch et al. show that eRNAs induce immediate early genes in neurons by facilitating the release of the negative elongation factor, NELF, from the promoter so that paused RNA polymerase II can engage in productive transcription.