Enhancer-derived RNAs: ‘spicing up’ transcription programs

Abstract

Recent reports established transcription of enhancerderived RNAs (eRNAs), while the evidence for their functional significance remained mostly speculative. Two recent reports published in Nature (Lam et al, 2013;Li et al, 2013) offer the first functional evidence for eRNA transcripts. These analyses further reveal an unexpected level of specificity in the regulation of adjacent mRNAs by eRNAs.Enhancers are genomic elements that have been implicated in the regulation of gene transcription for many years. They function by promoting transcriptional activity of promoter regions, generally from significant distances away, and in many cases they are the primary transcription factor binding site. Understanding the complex relationship between promoters and their enhancers has been a major focal point in recent times. The number of enhancers in a cellular context has been estimated to be 55 000 (Heintzman et al, 2009) and there is tissue-specific enhancer activity (Visel et al, 2009), implying that there is plasticity in determining what elements become enhancers within a specific cellular context.A surprising observation arising from analysis of enhancer elements was the finding that eRNAs are transcribed from the genomic sequence encompassing the enhancer. These findings resulted from the use of novel technical approaches for assessing non-coding RNAs, including GROseq (Core et al, 2008). This methodological approach was exploited to identify cell lineage-specific eRNAs. As examples, analysis of membrane depolarization in primary neuronal cultures revealed approximately 2000 eRNAs that were produced at enhancers, with a coincident enrichment of H3K4me1 marks and binding of both the co-activator CBP and RNA PolII. In many cases, the eRNAs produced from an individual enhancer were bidirectional and these correlated with expression levels of the adjacent mRNA (Kim et al, 2010), suggesting that expression of the eRNA and the neighbouring mRNA are linked. In oestrogen-stimulated breast cancer cells, a large number of eRNAs were induced within tens of minutes of ligand exposure from enhancer elements that were bound by oestrogen receptor (ER; Hah et al, 2011). These findings suggest that hormone stimulation results in expression of coding mRNAs that use enhancer elements for optimal transcriptional activity, while eRNAs are simultaneously transcribed from the distal enhancer elements themselves. In a similar system, activation of the androgen receptor in prostate cancer cells results in

Transcriptional, epigenetic and retroviral signatures identify regulatory regions involved in hematopoietic lineage commitment

“…A high proportion (40%) of unannotated DU CAGE promoters were marked by histone modifications typical of enhancers. These results support the hypothesis that a consistent fraction of novel CAGE promoters drives the expression of eRNAs, possibly involved in the regulation of proximal genes 49 50 51 52 53 54 and in the fine tuning of HSPC commitment. Moreover, a significant fraction of DU CAGE promoters overlapped with transposable elements, which play a role in developmental gene regulation and specification of cell fate 55 56 57 58 .…”

ICR Noncoding RNA Expression Controls Imprinting and DNA Replication at the Dlk1-Dio3 Domain

“…Like for other enhancers, it remains unknown how ncRNA sequences could be involved in regulating gene expression at distant promoters. A proposed hypothesis (Redmond and Carroll, 2013) is that enhancer-transcribed RNAs could transiently stabilize chromatin interactions between enhancers and promoters. Although the IG-DMR-RNA was indeed detected in cis as nuclear foci in stem cells, future work should explore whether specific RNAs transcribed from the IG-DMR have such a function.…”