Transcriptional control by enhancers and enhancer RNAs

Abstract

The regulation of gene expression is a fundamental cellular process and its misregulation is a key component of disease. Enhancers are one of the most salient regulatory elements in the genome and help orchestrate proper spatiotemporal gene expression during development, in homeostasis, and in response to signaling. Notably, molecular aberrations at enhancers, such as translocations and single nucleotide polymorphisms, are emerging as an important source of human variation and susceptibility to disease. Herein we discuss emerging paradigms addressing how genes are regulated by enhancers, common features of active enhancers, and how non-coding enhancer RNAs (eRNAs) can direct gene expression programs that underlie cellular phenotypes. We survey the current evidence, which suggests that eRNAs can bind to transcription factors, mediate enhancer-promoter interactions, influence RNA Pol II elongation, and act as decoys for repressive cofactors. Furthermore, we discuss current methodologies for the identification of eRNAs and novel approaches to elucidate their functions.

Functional Characterization of a Dual Enhancer/Promoter Regulatory Element Leading Human CD69 Expression

“…Firstly described in 2010 for the β-globin locus, enhancer transcription into non-coding RNA transcripts, termed enhancer derived RNAs (eRNAs), has rapidly become a widely accepted feature of all active enhancers (Andersson et al, 2014a), with a higher validation rate than conventional criteria, as histone modifications or DHSs (Lu et al, 2015). The CNS2 element is transcribed into two different eRNAs whose expression precedes CD69 promoter activation, thus resembling the kinetics described for this type of RNA molecules in different cell activation systems (Lewis et al, 2019). CNS2 eRNAs are not processed or polyadenylated, although a minority of eRNAs have been described to be processed and to have termination sites (Koch et al, 2011;Andersson et al, 2014b;Tsai et al, 2018).…”

“…Recently, RNA molecules transcribed from enhancers, termed enhancer-derived RNAs (eRNAs), have been found to play an active role in the development of the enhancer function (Lam et al, 2014). Enhancers are frequently bidirectionally transcribed into non-coding RNAs with short half-lives, which are generally not spliced or polyadenylated, and are typically short (1-2 Kb) and retained in nuclear fractions (Lewis et al, 2019). These molecules, in addition to be markers of active enhancers (Andersson et al, 2014a), act in cis or trans (interchromosomally) (Tsai et al, 2018) in regulating the expression of target genes.…”

“…These molecules, in addition to be markers of active enhancers (Andersson et al, 2014a), act in cis or trans (interchromosomally) (Tsai et al, 2018) in regulating the expression of target genes. Depletion of eRNAs often results in downregulation of nearby gene expression and, although different mechanisms of action have been proposed (Lewis et al, 2019), several studies support that this effect is due to the inhibition of chromatin looping, which brings promoters and distal regulatory elements into contact, as revealed by proximity ligation techniques (3C, 4C and HiC) (Hsieh et al, 2014;Pnueli et al, 2015).…”

Disease-Causing Mutations and Rearrangements in Long Non-coding RNA Gene Loci

“…In line with the critical roles of enhancers in the orchestration of gene expression in and outside of insulated chromatin domains [topologically associating domains (TADs); Fanucchi and Mhlanga, 2017], nucleotide variants and disruptions affecting enhancers, and potentially the transcription of eRNAs and lncRNAs generated from these regions, have been implicated in various diseases. This ranges from autoimmune diseases to mental disorders and cancer (Farh et al, 2015;Javierre et al, 2016;Teppo et al, 2016;Ren et al, 2017;Hauberg et al, 2019;Isoda et al, 2019;Lewis et al, 2019;Chen et al, 2020b;Yamagata et al, 2020). Thus, beyond lncRNAs encoded within coding gene regions or seemingly empty genomic space, genetic variation in transcribed regulatory DNA units, such as enhancers, contributes to human diseases.…”

Prioritization of osteoporosis-associated GWAS SNPs using epigenomics and transcriptomics

“…Therefore, rs7733331 is an especially attractive candidate for a BMD-regulatory SNP that might affect enhancer-associated NPR3 transcription through a novel lincRNA gene in cis. (34) LGR4 is associated with a BMD-risk Tier-1 SNP downstream of another protein-coding gene Leucine rich G protein-coupled receptor 4 (LGR4/GPR48) was associated with one Tier-1 SNP, rs10835153. This gene encodes a cell membrane receptor that can regulate Wnt signaling and is implicated in both embryonic bone development and postnatal bone remodeling.…”