Enhancers are cis-regulatory elements in the genome that cooperate with promoters to control target gene transcription. Unlike promoters, enhancers are not necessarily adjacent to target genes and can exert their functions regardless of enhancer orientations, positions and spatial segregations from target genes. Thus, for a long time, the question as to how enhancers act in a temporal and spatial manner attracted considerable attention. The recent discovery that enhancers are also abundantly transcribed raises interesting questions about the exact roles of enhancer RNA (eRNA) in gene regulation. In this review, we highlight the process of enhancer transcription and the diverse features of eRNA. We review eRNA functions, which include enhancer-promoter looping, chromatin modifying, and transcription regulating. As eRNA are transcribed from active enhancers, they exhibit tissue and lineage specificity, and serve as markers of cell state and function. Finally, we discuss the unique relationship between eRNA and super enhancers in phase separation wherein eRNA may contribute significantly to cell fate decisions.

/pdf/diversity-and-emerging-roles-of-enhancer-rna-in-regulation-3jejp4wjg8.pdf

Diversity and Emerging Roles of Enhancer RNA in Regulation of Gene Expression and Cell Fate

Enhancers are noncoding DNA elements that are present upstream or downstream of a gene to control its spatial and temporal expression. Specific histone modifications, such as monomethylation on histone H3 lysine 4 (H3K4me1) and H3K27ac, have been widely used to assign enhancer regions in mammalian genomes. In recent years, emerging evidence suggests that active enhancers are bidirectionally transcribed to produce enhancer RNAs (eRNAs). This finding not only adds a new reliable feature to define enhancers but also raises a fundamental question of how eRNAs function to activate transcription. Although some believe that eRNAs are merely transcriptional byproducts, many studies have demonstrated that eRNAs execute crucial tasks in regulating chromatin conformation and transcription activation. In this review, we summarize the current understanding of eRNAs from their biogenesis, functions, and regulation to their pathological significance. Additionally, we discuss the challenges and possible mechanisms of eRNAs in regulated transcription.

Enhancer RNA: biogenesis, function, and regulation.

Gapmers are antisense oligonucleotides composed of a central DNA segment flanked by nucleotides of modified chemistry. Hybridizing with transcripts by sequence complementarity, gapmers recruit ribonuclease H and induce target RNA degradation. Since its concept first emerged in the 1980s, much work has gone into developing gapmers for use in basic research and therapy. These include improvements in gapmer chemistry, delivery, and therapeutic safety. Gapmers have also successfully entered clinical trials for various genetic disorders, with two already approved by the U.S. Food and Drug Administration for the treatment of familial hypercholesterolemia and transthyretin amyloidosis-associated polyneuropathy. Here, we review the events surrounding the early development of gapmers, from conception to their maturity, and briefly conclude with perspectives on their use in therapy.

Invention and Early History of Gapmers.

Enhancer RNAs (eRNAs) are a class of non-coding RNAs transcribed from enhancers. As the markers of active enhancers, eRNAs play important roles in gene regulation and are associated with various complex traits and characteristics. With increasing attention to eRNAs, numerous eRNAs have been identified in different human tissues. However, the expression landscape, regulatory network and potential functions of eRNAs in animals have not been fully elucidated. Here, we systematically characterized 185 177 eRNAs from 5085 samples across 10 species by mapping the RNA sequencing data to the regions of known enhancers. To explore their potential functions based on evolutionary conservation, we investigated the sequence similarity of eRNAs among multiple species. In addition, we identified the possible associations between eRNAs and transcription factors (TFs) or nearby genes to decipher their possible regulators and target genes, as well as characterized trait-related eRNAs to explore their potential functions in biological processes. Based on these findings, we further developed Animal-eRNAdb (http://gong_lab.hzau.edu.cn/Animal-eRNAdb/), a user-friendly database for data searching, browsing and downloading. With the comprehensive characterization of eRNAs in various tissues of different species, Animal-eRNAdb may greatly facilitate the exploration of functions and mechanisms of eRNAs.

Animal-eRNAdb: a comprehensive animal enhancer RNA database.

Enhancer can transcribe RNAs, however, most of them were neglected in traditional RNA-seq analysis workflow Here, we developed a Pipeline for Enhancer Transcription (PET, http://fun-scienceclub/PET) for quantifying enhancer RNAs (eRNAs) from RNA-seq By applying this pipeline on lung cancer samples and cell lines, we showed that the transcribed enhancers are enriched with histone marks and transcription factor motifs (JUNB, Hand1-Tcf3 and GATA4) By training a machine learning model, we demonstrate that enhancers can predict prognosis better than their nearby genes Integrating the Hi-C, ChIP-seq and RNA-seq data, we observe that transcribed enhancers associate with cancer hallmarks or oncogenes, among which LcsMYC-1 (Lung cancer-specific MYC eRNA-1) potentially supports MYC expression Surprisingly, a significant proportion of transcribed enhancers contain small protein-coding open reading frames (sORFs) and can be translated into microproteins Our study provides a computational method for eRNA quantification and deepens our understandings of the DNA, RNA and protein nature of enhancers

Multi-omics analysis reveals the functional transcription and potential translation of enhancers.

Background: Enhancers are genomic regulatory elements conferring spatiotemporal and signal-dependent control of gene expression. Recent evidence suggests that enhancers can generate noncoding enhan...

https://serval.unil.ch/resource/serval:BIB_BAE7C7F2C66F.P001/REF.pdf

Inhibition of the Hypoxia-Inducible Factor 1α-Induced Cardiospecific HERNA1 Enhance-Templated RNA Protects From Heart Disease.

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Inhibition of the Hypoxia-Inducible Factor 1α-Induced Cardiospecific HERNA1 Enhance-Templated RNA Protects From Heart Disease.