Enhancer RNAs: a missing regulatory layer in gene transcription

Enhancers and super-enhancers exert indispensable roles in maintaining cell identity through spatiotemporally regulating gene transcription. Meanwhile, active enhancers and super-enhancers also produce transcripts termed enhancer RNAs (eRNAs) from their DNA elements. Although enhancers have been identified for more than 30 years, widespread transcription from enhancers are just discovered by genome-wide sequencing and considered as the key to understand longstanding questions in gene transcription. RNA-transcribed enhancers are marked by histone modifications such as H3K4m1/2 and H3K27Ac, and enriched with transcription regulatory factors such as LDTFs, P300, CBP, BRD4 and MED1. Those regulatory factors might constitute a Mega-Trans-like complex to potently activate enhancers. Compared to mRNAs, eRNAs are quite unstable and play roles at local. Functionally, it has been shown that eRNAs promote formation of enhancer-promoter loops. Several studies also demonstrated that eRNAs help the binding of RNA polymerase II (RNAPII) or transition of paused RNAPII by de-association of the negative elongation factor (NELF) complex. Nevertheless, these proposed mechanisms are not universally accepted and still under controversy. Here, we comprehensively summarize the reported findings and make perspectives for future exploration. We also believe that super-enhancer derived RNAs (seRNAs) might be informative to understand the nature of super-enhancers.