Journal Article

Enhancers as non-coding RNA transcription units: recent insights and future perspectives

Rosenfeld, Michael G., Notani, Dimple, Li, Wenbo

2016

Overview

Key Points Enhancers are distal regulatory genomic elements that determine spatiotemporal and quantitative gene transcription programmes in response to developmental or environmental cues. Global transcriptomic and (epi)genomic advances have found that enhancers are pervasively transcribed into non-coding RNAs (ncRNAs), which are named enhancer RNAs (eRNAs). The expression levels of eRNAs are highly correlated with the activity of the functional enhancers, both in developmental and rapid signal-regulated transcriptional programmes. eRNAs bear several common and unique features compared to other long ncRNAs or coding mRNAs. Heterogeneity of eRNAs exists in terms of both transcriptional processes and RNA properties, which might be linked to their functional diversity. There is evidence supporting a functional role of both the eRNA transcripts per se, and the act of transcription, in the activation of target coding genes. However, for the large majority of eRNAs in the mammalian genome, evidence of their functional roles is still limited. Mechanisms underlying the roles of specific eRNAs include modulating the chromatin accessibility of cognate promoters, stabilizing enhancer–promoter interactions, trapping transcription factors on genomic sites, and regulating the RNA polymerase II pause release at cognate promoters. The act of enhancer transcription may facilitate histone modifications, remodel large areas of chromatin and induce transcriptional interference. Enhancer transcription may take part in generating several important biological phenomena, including transcription-dependent R-loops, genomic mutations and instability at enhancers, and potentially facilitate new gene birth during evolution. Further evidence is needed to fully understand the functions of different categories of enhancers as transcription units and the roles of eRNAs per se , in gene regulation, development and disease. The observation that many, if not all, functional enhancers generate non-coding enhancer RNAs (eRNAs) has raised critical questions regarding the potential biological roles of the enhancer transcription process and, indeed, of eRNAs. This article reviews fundamental insights into the inter-regulation of enhancers and promoters and discusses unresolved questions regarding the functional role of enhancers as transcription units in genome regulation. Networks of regulatory enhancers dictate distinct cell identities and cellular responses to diverse signals by instructing precise spatiotemporal patterns of gene expression. However, 35 years after their discovery, enhancer functions and mechanisms remain incompletely understood. Intriguingly, recent evidence suggests that many, if not all, functional enhancers are themselves transcription units, generating non-coding enhancer RNAs. This observation provides a fundamental insight into the inter-regulation between enhancers and promoters, which can both act as transcription units; it also raises crucial questions regarding the potential biological roles of the enhancer transcription process and non-coding enhancer RNAs. Here, we review research progress in this field and discuss several important, unresolved questions regarding the roles and mechanisms of enhancers in gene regulation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/726/2102 / 631/337/384 / 631/337/572 / Agriculture / Animal Genetics and Genomics / Animals / Biomedicine / Cancer Research / Enhancer Elements, Genetic / Gene Expression Regulation / Gene Function / Genes / Genetic research / Genetic transcription / Genomic Instability / Human Genetics / Humans / Models, Genetic / Multigene Family / Promoter Regions, Genetic / Properties / review-article / RNA Processing, Post-Transcriptional / RNA, Untranslated - genetics / RNA, Untranslated - metabolism / Transcription Factors - metabolism / Transcription, Genetic