# Enhancer RNA

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Type of non-coding RNA molecule

"ERNA" redirects here. For other uses, see [ERNA (disambiguation)](/source/ERNA_(disambiguation)).

**Enhancer RNAs** (eRNAs) represent a class of relatively long [non-coding RNA](/source/Non-coding_RNA) molecules (50–2000 nucleotides) transcribed from the DNA sequence of [enhancer](/source/Enhancer_(genetics)) regions. They were first detected in 2010 through the use of genome-wide techniques such as [RNA-seq](/source/RNA-seq) and [ChIP-seq](/source/ChIP-seq).[1][2] eRNAs can be subdivided into two main classes: 1D eRNAs and 2D eRNAs, which differ primarily in terms of their size, [polyadenylation](/source/Polyadenylation) state, and transcriptional directionality.[3] The expression of a given eRNA correlates with the activity of its corresponding enhancer in target genes.[4] Increasing evidence suggests that eRNAs actively play a role in [transcriptional regulation](/source/Transcriptional_regulation) in [cis](/source/Cis-acting) and in [trans](/source/Trans-acting), and while their mechanisms of action remain unclear, a few models have been proposed.[3]

## Discovery

[Enhancers](/source/Enhancers) as sites of extragenic [transcription](/source/Transcription_(genetics)) were initially discovered in genome-wide studies that identified enhancers as common regions of [RNA polymerase II](/source/RNA_polymerase_II) (RNA pol II) binding and [non-coding RNA](/source/Non-coding_RNA) transcription.[1][2] The level of RNA pol II–enhancer interaction and RNA transcript formation were found to be highly variable among these initial studies. Using explicit [chromatin](/source/Chromatin) signature peaks, a significant proportion (~70%) of [extragenic](/source/Extragenic) RNA Pol II transcription start sites were found to overlap enhancer sites in [murine](/source/Murine) [macrophages](/source/Macrophages).[5] Out of 12,000 [neuronal](/source/Neuronal) enhancers in the [mouse](/source/Mouse) [genome](/source/Genome), almost 25% of the sites were found to bind RNA Pol II and generate [transcripts](/source/Transcription_(genetics)).[6] In parallel studies, 4,588 high confidence [extragenic](/source/Extragenic) RNA Pol II binding sites were identified in murine macrophages stimulated with the inflammatory mediater [lipopolysaccharide](/source/Lipopolysaccharide) to induce transcription.[2] These eRNAs, unlike messenger RNAs (mRNAs), lacked modification by [polyadenylation](/source/Polyadenylation), were generally short and non-coding, and were bidirectionally transcribed. Later studies revealed the transcription of another type of eRNAs, generated through unidirectional transcription, that were longer and contained a [poly A tail](/source/Poly_A_tail).[7] Furthermore, eRNA levels were correlated with [mRNA](/source/MRNA) levels of nearby [genes](/source/Genes), suggesting the potential regulatory and functional role of these non-coding enhancer [RNA](/source/RNA) [molecules](/source/Molecules).[1]

## Biogenesis

eRNA Biogenesis

### Summary

eRNAs are transcribed from [DNA sequences](/source/DNA_sequences) [upstream](/source/Upstream_and_downstream_(DNA)) and [downstream](/source/Upstream_and_downstream_(DNA)) of [extragenic](/source/Extragenic) [enhancer](/source/Enhancer_(genetics)) regions.[8] Previously, several model enhancers have demonstrated the capability to directly recruit [RNA Pol II](/source/RNA_Pol_II) and general [transcription factors](/source/Transcription_factors) and form the pre-initiation complex (PIC) prior to the [transcription start site](/source/Transcription_(genetics)) at the [promoter](/source/Promoter_(genetics)) of [genes](/source/Genes). In certain [cell](/source/Cell_(biology)) types, activated enhancers have demonstrated the ability to both recruit RNA Pol II and also provide a template for active [transcription](/source/Transcription_(genetics)) of their local [sequences](/source/Sequences).[2][1]

Depending on the directionality of transcription, enhancer regions generate two different types of non-coding [transcripts](/source/Transcription_(genetics)), 1D-eRNAs and 2D-eRNAs. The nature of the pre-initiation complex and specific transcription factors recruited to the enhancer may control the type of eRNAs generated. After transcription, the majority of eRNAs remain in the [nucleus](/source/Cell_nucleus).[9] In general, eRNAs are very unstable and actively degraded by the nuclear [exosome](/source/Exosome_complex). Not all enhancers are transcribed, with non-transcribed enhancers greatly outnumbering the transcribed ones in the order of magnitude of dozens of thousands in every given [cell](/source/Cell_(biology)) type.[5]

### 1D eRNAs

In most cases, unidirectional [transcription](/source/Transcription_(genetics)) of [enhancer](/source/Enhancer_(genetics)) regions generates long (>4kb) and polyadenylated eRNAs. Enhancers that generate polyA+ eRNAs have a lower [H3K4me1](/source/H3K4me1)/me3 ratio in their [chromatin](/source/Chromatin) signature than 2D-eRNAs.[7] PolyA+ eRNAs are distinct from long multiexonic poly transcripts (meRNAs) that are generated by transcription initiation at intragenic enhancers. These long non-coding RNAs, which accurately reflect the host [gene](/source/Gene)'s structure except for the alternative first [exon](/source/Exon), display poor coding potential.[10] As a result, polyA+ 1D-eRNAs may represent a mixed group of true enhancer-templated RNAs and multiexonic RNAs.

### 2D eRNAs

Bidirectional [transcription](/source/Transcription_(genetics)) at [enhancer](/source/Enhancer_(genetics)) sites generates comparatively shorter (0.5-2kb) and non-polyadenylated eRNAs. Enhancers that generate polyA- eRNAs have a [chromatin](/source/Chromatin) signature with a higher H3K4me1/me3 ratio than 1D-eRNAs. In general, enhancer transcription and production of bidirectional eRNAs demonstrate a strong correlation of enhancer activity on gene transcription.[11]

## Frequency and timing of eRNA expression

Arner et al.[12] identified 65,423 [transcribed](/source/Transcription_(biology)) enhancers (producing eRNA) among 33 different cell types under different conditions and different timings of stimulation. The transcription of enhancers generally preceded transcription of [transcription factors](/source/Transcription_factor) which, in turn, generally preceded [messenger RNA](/source/Messenger_RNA) (mRNA) transcription of genes.

Carullo et al.[13] examined one particular cell type, [neurons](/source/Neurons) (from primary neuron cultures). They exhibited 28,492 putative enhancers generating eRNAs. These eRNAs were often transcribed from both strands of the enhancer DNA in opposite directions. Carullo et al.[13] used these cultured neurons to examine the timing of specific enhancer eRNAs compared to the [mRNAs](/source/Messenger_RNA) of their target genes. The cultured neurons were activated and RNA was isolated from those neurons at 0, 3.75, 5, 7.5, 15, 30, and 60 minutes after activation. In these experimental conditions, they found that 2 of the 5 enhancers of the [immediate early gene](/source/Immediate_early_gene) (IEG) *FOS*, that is FOS enhancer 1 and FOS enhancer 3, became activated and initiated transcription of their eRNAs (eRNA1 and eRNA3). FOS eRNA1 and eRNA3 were significantly up-regulated within 7.5 minutes, whereas FOS mRNA was only upregulated 15 minutes after stimulation. Similar patterns occurred at IEGs *FOSb* and *NR4A1*, indicating that for many IEGs, eRNA induction precedes mRNA induction in response to neuronal activation.

While some enhancers can activate their target [promoters](/source/Promoter_(genetics)) at their target genes without transcribing eRNA, most active enhancers do transcribe eRNA during activation of their target promoters.[14]

## Functions of eRNA found in the period 2013 to 2021

The functions for eRNA described below have been reported in diverse biological systems, often demonstrated with a small number of specific enhancer-target gene pairs. It is not clear to what extent the functions of eRNA described here can be generalized to most eRNAs.

### eRNAs in loop formation

 **Regulatory elements, including [Negative elongation factor](/source/Negative_elongation_factor) (NELF) and enhancer RNA (eRNA) control transcription of a gene into messenger RNA in [metazoans](/source/Metazoans) (animals).** An active enhancer regulatory region of DNA is enabled to interact with the promoter DNA region of its target gene by the formation of a chromosome loop. This can initiate messenger RNA (mRNA) synthesis by RNA polymerase II (RNAP II) bound to the promoter at the transcription start site of the gene. The loop is stabilized by one architectural protein anchored to the enhancer and one anchored to the promoter and these proteins are joined to form a dimer (red zigzags). Specific regulatory transcription factors bind to DNA sequence motifs on the enhancer. General transcription factors bind to the promoter. When a transcription factor is activated by a signal (here indicated as phosphorylation shown by a small red star on a transcription factor on the enhancer) the enhancer is activated and can now activate its target promoter. The active enhancer is transcribed on each strand of DNA in opposite directions by bound RNAP IIs. Mediator (a complex consisting of about 26 proteins in an interacting structure) communicates regulatory signals from the enhancer DNA-bound transcription factors to the promoter. NELF, in complex with DSIF and RNAP II, can pause transcription. Interaction of eRNA with NELF may release NELF and allow productive elongation of mRNA.  NELF can also be released if it is phosphorylated by [P-TEFb](/source/P-TEFb)

The chromosome loops shown in the figure, bringing an enhancer to the promoter of its target gene, may be directed and formed by the eRNA transcribed from the enhancer after the enhancer is activated.

A transcribed enhancer RNA (eRNA) interacting with the complex of [Mediator proteins](/source/Mediator_(coactivator)) (see Figure), especially Mediator subunit 12 ([MED12](/source/MED12)), appears to be essential in forming the chromosome loop that brings the enhancer into close association with the promoter of the target gene of the enhancer in the case of five genes studied by Lai et al.[15][16][17] Hou and Kraus,[18] describe two other studies reporting similar results. Arnold et al.[19] review another 5 instances where eRNA is active in forming the enhancer-promoter loop.

### eRNAs interact with proteins to affect transcription

One well-studied eRNA is the eRNA of the enhancer that interacts with the promoter of the prostate specific antigen (PSA) gene.[20] The PSA eRNA is strongly up-regulated by the [androgen receptor](/source/Androgen_receptor). High PSA eRNA then has a domino effect. PSA eRNA binds to and activates the positive transcription elongation factor [P-TEFb](/source/P-TEFb) protein complex which can then phosphorylate [RNA polymerase II](/source/RNA_polymerase_II) (RNAP II), initiating its activity in producing [mRNA](/source/Messenger_RNA). P-TEFb can also phosphorylate the [negative elongation factor](/source/Negative_elongation_factor) NELF (which pauses RNAP II within 60 nucleotides after mRNA initiation begins). Phosphorylated NELF is released from RNAP II, then allowing RNAP II to have productive mRNA progression (see Figure). Up-regulated PSA eRNA thereby increases expression of 586 androgen receptor-responsive genes. Knockdown of PSA eRNA or deleting a set of nucleotides from PSA eRNA causes decreased presence of phosphorylated (active) RNAP II at these genes causing their reduced transcription.

The [negative elongation factor](/source/Negative_elongation_factor) NELF protein can also be released from its interaction with RNAP II by direct interaction with some eRNAs. Schaukowitch et al.[21] showed that the eRNAs of two [immediate early genes](/source/Immediate_early_gene) (IEGs) directly interacted with the NELF protein to release NELF from the RNAP II paused at the promoters of these two genes, allowing these two genes to then be expressed.

In addition, eRNAs appear to interact with as many as 30 other proteins.[19][17][18]

## Proposed mechanisms of function up until 2013

Proposed Mechanisms of eRNA Function

The notions that not all [enhancers](/source/Enhancers) are transcribed at the same time and that eRNA [transcription](/source/Transcription_(genetics)) correlates with enhancer-specific activity support the idea that individual eRNAs carry distinct and relevant biological functions.[3] However, there is still no [consensus](/source/Scientific_consensus) on the functional significance of eRNAs. Furthermore, eRNAs can easily be degraded through [exosomes](/source/Exosome_complex) and [nonsense-mediated decay](/source/Nonsense-mediated_decay), which limits their potential as important transcriptional regulators.[22] To date, four main models of eRNA function have been proposed,[3] each supported by different lines of [experimental](/source/Experimental) [evidence](/source/Evidence).

### Transcriptional Noise

Since multiple studies have shown that [RNA Pol II](/source/RNA_Pol_II) can be found at a very large number of [extragenic](/source/Extragenic) regions, it is possible that eRNAs simply represent the product of random "leaky" [transcription](/source/Transcription_(genetics)) and carry no functional significance.[5] The non-specific activity of RNA Pol II would therefore allow [extragenic](/source/Extragenic) transcriptional noise at sites where [chromatin](/source/Chromatin) is already in an open and transcriptionally competent state. This would explain even tissue-specific eRNA expression[23] as open sites are tissue-specific as well.

### Transcription-dependent effects

[RNA Pol II](/source/RNA_Pol_II)-mediated [gene](/source/Gene) [transcription](/source/Transcription_(genetics)) induces a local opening of [chromatin](/source/Chromatin) state through the recruitment of [histone acetyltransferases](/source/Histone_acetyltransferases) and other [histone](/source/Histone) modifiers that promote [euchromatin](/source/Euchromatin) formation. It was proposed that the presence of these [enzymes](/source/Enzymes) could also induce an opening of [chromatin](/source/Chromatin) at [enhancer](/source/Enhancer_(genetics)) regions, which are usually present at distant locations but can be recruited to target [genes](/source/Genes) through looping of [DNA](/source/DNA).[24] In this model, eRNAs are therefore expressed in response to [RNA Pol II](/source/RNA_Pol_II) transcription and therefore carry no [biological](/source/Biological) function.

### Functional activity in cis

While the two previous models implied that eRNAs were not functionally relevant, this mechanism states that eRNAs are functional [molecules](/source/Molecules) that exhibit [cis](/source/Cis-acting) activity. In this model, eRNAs can locally recruit [regulatory](/source/Regulatory) [proteins](/source/Proteins) at their own site of synthesis. Supporting this hypothesis, transcripts originating from [enhancers](/source/Enhancers) upstream of the [Cyclin D1](/source/Cyclin_D1) gene are thought to serve as adaptors for the recruitment of [histone acetyltransferases](/source/Histone_acetyltransferases). It was found that depletion of these eRNAs led to Cyclin D1 transcriptional silencing.[9]

### Functional activity in trans

The last model involves [transcriptional](/source/Transcriptional) regulation by eRNAs at distant [chromosomal](/source/Chromosomal) locations. Through the differential recruitment of [protein](/source/Protein) [complexes](/source/Multiprotein_complex), eRNAs can affect the transcriptional competency of specific [loci](/source/Locus_(genetics)). Evf-2 represents a good example of such [trans](/source/Trans-acting) regulatory eRNA as it can induce the expression of Dlx2, which in turn can increase the activity of the Dlx5 and Dlx6 [enhancers](/source/Enhancers).[25] [Trans-acting](/source/Trans-acting) eRNAs might also be working in [cis](/source/Cis-acting), and vice versa.

## Experimental detection

The detection of eRNAs is fairly recent (2010) and has been made possible through the use of genome-wide investigation techniques such as [RNA sequencing](/source/RNA_sequencing) (RNA-seq) and chromatin immunoprecipitation-sequencing ([ChIP-seq](/source/ChIP-seq)).[1] RNA-seq permits the direct identification of eRNAs by matching the detected transcript to the corresponding [enhancer](/source/Enhancer_(genetics)) sequence through [bioinformatic](/source/Bioinformatic) analyses.[26][4] ChIP-seq represents a less direct way to assess enhancer [transcription](/source/Transcription_(genetics)) but can also provide crucial information as specific [chromatin](/source/Chromatin) marks are associated with active enhancers.[27] Although some data remain controversial, the consensus in the literature is that the best combination of histone post-translational modifications at active enhancers is made of [H2AZ](/source/H2AZ), [H3K27ac](/source/H3K27ac), and a high ratio of H3K4me1 over [H3K4me3](/source/H3K4me3).[27][28][29] ChIP experiments can also be conducted with [antibodies](/source/Antibodies) that recognize [RNA Pol II](/source/RNA_Pol_II), which can be found at sites of active [transcription](/source/Transcription_(genetics)).[5] The experimental detection of eRNAs is complicated by their low [endogenous](/source/Endogenous) stability conferred by [exosome](/source/Exosome_complex) degradation and [nonsense-mediated decay](/source/Nonsense-mediated_decay).[22] A comparative study showed that assays enriching for [capped](/source/Five-prime_cap) and nascent RNAs (with strategies like nuclei [run-on](/source/Nuclear_run-on) and size selection) could capture more eRNAs compared to canonical RNA-seq.[30] These assays include Global/Precision Run-on with cap-selection (GRO/PRO-cap), capped-small RNA-seq (csRNA-seq), Native Elongating Transcript-Cap Analysis of Gene Expression (NET-CAGE), and Precision Run-On sequencing (PRO-seq).[31] Nonetheless, the fact that eRNAs tend to be expressed from active enhancers might make their detection a useful tool to distinguish between active and inactive enhancers.

## Implications in development and disease

Evidence that eRNAs cause downstream effects on the [efficiency](/source/Efficiency) of enhancer activation and gene transcription suggests its functional capabilities and potential importance.[4] The [transcription factor](/source/Transcription_factor) [p53](/source/P53) has been demonstrated to bind [enhancer](/source/Enhancer_(genetics)) regions and generate eRNAs in a p53-dependent manner.[32] In [cancer](/source/Cancer), p53 plays a central role in [tumor suppression](/source/Tumor_suppression) as [mutations](/source/Mutations) of the [gene](/source/Gene) are shown to appear in 50% of [tumors](/source/Tumors).[33] These p53-bound enhancer regions (p53BERs) are shown to interact with multiple local and distal gene targets involved in [cell](/source/Cell_(biology)) [proliferation](/source/Cell_proliferation) and survival. Furthermore, eRNAs generated by the activation of p53BERs are shown to be required for efficient [transcription](/source/Transcription_(genetics)) of the p53 target genes, indicating the likely important regulatory role of eRNAs in tumor suppression and cancer. Generally, mutations in eRNA have been shown to demonstrate similar phenotypic behavior in oncogenesis as compared to protein-coding RNA.[34]

Variations in enhancers have been implicated in human [disease](/source/Disease) but a [therapeutic](/source/Therapeutic) approach to manipulate enhancer activity is currently not available. With the emergence of eRNAs as important components in enhancer activity, powerful therapeutic tools such as [RNAi](/source/RNAi) may provide promising routes to target disruption of gene expression.

## References

1. ^ [***a***](#cite_ref-Kim2010_1-0) [***b***](#cite_ref-Kim2010_1-1) [***c***](#cite_ref-Kim2010_1-2) [***d***](#cite_ref-Kim2010_1-3) [***e***](#cite_ref-Kim2010_1-4) Kim TK, Hemberg M, Gray JM, Costa AM, Bear DM, Wu J, et al. (May 2010). ["Widespread transcription at neuronal activity-regulated enhancers"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3020079). *Nature*. **465** (7295): 182–187. [Bibcode](/source/Bibcode_(identifier)):[2010Natur.465..182K](https://ui.adsabs.harvard.edu/abs/2010Natur.465..182K). [doi](/source/Doi_(identifier)):[10.1038/nature09033](https://doi.org/10.1038%2Fnature09033). [PMC](/source/PMC_(identifier)) [3020079](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3020079). [PMID](/source/PMID_(identifier)) [20393465](https://pubmed.ncbi.nlm.nih.gov/20393465).

1. ^ [***a***](#cite_ref-:0_2-0) [***b***](#cite_ref-:0_2-1) [***c***](#cite_ref-:0_2-2) [***d***](#cite_ref-:0_2-3) De Santa F, Barozzi I, Mietton F, Ghisletti S, Polletti S, Tusi BK, et al. (May 2010). ["A large fraction of extragenic RNA pol II transcription sites overlap enhancers"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867938). *PLOS Biology*. **8** (5) e1000384. [doi](/source/Doi_(identifier)):[10.1371/journal.pbio.1000384](https://doi.org/10.1371%2Fjournal.pbio.1000384). [PMC](/source/PMC_(identifier)) [2867938](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867938). [PMID](/source/PMID_(identifier)) [20485488](https://pubmed.ncbi.nlm.nih.gov/20485488).

1. ^ [***a***](#cite_ref-Natoli2012_3-0) [***b***](#cite_ref-Natoli2012_3-1) [***c***](#cite_ref-Natoli2012_3-2) [***d***](#cite_ref-Natoli2012_3-3) Natoli G, Andrau JC (2012). "Noncoding transcription at enhancers: general principles and functional models". *Annual Review of Genetics*. **46**: 1–19. [doi](/source/Doi_(identifier)):[10.1146/annurev-genet-110711-155459](https://doi.org/10.1146%2Fannurev-genet-110711-155459). [PMID](/source/PMID_(identifier)) [22905871](https://pubmed.ncbi.nlm.nih.gov/22905871).

1. ^ [***a***](#cite_ref-:1_4-0) [***b***](#cite_ref-:1_4-1) [***c***](#cite_ref-:1_4-2) Burren OS, Rubio García A, Javierre BM, Rainbow DB, Cairns J, Cooper NJ, et al. (September 2017). ["Chromosome contacts in activated T cells identify autoimmune disease candidate genes"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584004). *Genome Biology*. **18** (1) 165. [doi](/source/Doi_(identifier)):[10.1186/s13059-017-1285-0](https://doi.org/10.1186%2Fs13059-017-1285-0). [PMC](/source/PMC_(identifier)) [5584004](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584004). [PMID](/source/PMID_(identifier)) [28870212](https://pubmed.ncbi.nlm.nih.gov/28870212).

1. ^ [***a***](#cite_ref-De_Santa2010_5-0) [***b***](#cite_ref-De_Santa2010_5-1) [***c***](#cite_ref-De_Santa2010_5-2) [***d***](#cite_ref-De_Santa2010_5-3) De Santa F, Barozzi I, Mietton F, Ghisletti S, Polletti S, Tusi BK, et al. (May 2010). Mattick JS (ed.). ["A large fraction of extragenic RNA pol II transcription sites overlap enhancers"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867938). *PLOS Biology*. **8** (5) e1000384. [doi](/source/Doi_(identifier)):[10.1371/journal.pbio.1000384](https://doi.org/10.1371%2Fjournal.pbio.1000384). [PMC](/source/PMC_(identifier)) [2867938](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867938). [PMID](/source/PMID_(identifier)) [20485488](https://pubmed.ncbi.nlm.nih.gov/20485488).

1. **[^](#cite_ref-6)** Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD, et al. (March 2007). "Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome". *Nature Genetics*. **39** (3): 311–318. [doi](/source/Doi_(identifier)):[10.1038/ng1966](https://doi.org/10.1038%2Fng1966). [PMID](/source/PMID_(identifier)) [17277777](https://pubmed.ncbi.nlm.nih.gov/17277777). [S2CID](/source/S2CID_(identifier)) [1595885](https://api.semanticscholar.org/CorpusID:1595885).

1. ^ [***a***](#cite_ref-Koch2011_7-0) [***b***](#cite_ref-Koch2011_7-1) Koch F, Fenouil R, Gut M, Cauchy P, Albert TK, Zacarias-Cabeza J, et al. (July 2011). "Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters". *Nature Structural & Molecular Biology*. **18** (8): 956–963. [doi](/source/Doi_(identifier)):[10.1038/nsmb.2085](https://doi.org/10.1038%2Fnsmb.2085). [PMID](/source/PMID_(identifier)) [21765417](https://pubmed.ncbi.nlm.nih.gov/21765417). [S2CID](/source/S2CID_(identifier)) [12778976](https://api.semanticscholar.org/CorpusID:12778976).

1. **[^](#cite_ref-8)** Fedoseeva DM, Kretova OV, Tchurikov NA (2012). "Molecular analysis of enhancer RNAs and chromatin modifications in the region of their synthesis in Drosophila cells possessing genetic constructs". *Doklady. Biochemistry and Biophysics*. **442**: 7–11. [doi](/source/Doi_(identifier)):[10.1134/S1607672912010012](https://doi.org/10.1134%2FS1607672912010012). [PMID](/source/PMID_(identifier)) [22419084](https://pubmed.ncbi.nlm.nih.gov/22419084). [S2CID](/source/S2CID_(identifier)) [14304312](https://api.semanticscholar.org/CorpusID:14304312).

1. ^ [***a***](#cite_ref-Wang2008_9-0) [***b***](#cite_ref-Wang2008_9-1) Wang X, Arai S, Song X, Reichart D, Du K, Pascual G, et al. (July 2008). ["Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823488). *Nature*. **454** (7200): 126–130. [Bibcode](/source/Bibcode_(identifier)):[2008Natur.454..126W](https://ui.adsabs.harvard.edu/abs/2008Natur.454..126W). [doi](/source/Doi_(identifier)):[10.1038/nature06992](https://doi.org/10.1038%2Fnature06992). [PMC](/source/PMC_(identifier)) [2823488](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823488). [PMID](/source/PMID_(identifier)) [18509338](https://pubmed.ncbi.nlm.nih.gov/18509338).

1. **[^](#cite_ref-10)** Kowalczyk MS, Hughes JR, Garrick D, Lynch MD, Sharpe JA, Sloane-Stanley JA, et al. (February 2012). ["Intragenic enhancers act as alternative promoters"](https://doi.org/10.1016%2Fj.molcel.2011.12.021). *Molecular Cell*. **45** (4): 447–458. [doi](/source/Doi_(identifier)):[10.1016/j.molcel.2011.12.021](https://doi.org/10.1016%2Fj.molcel.2011.12.021). [hdl](/source/Hdl_(identifier)):[2318/97658](https://hdl.handle.net/2318%2F97658). [PMID](/source/PMID_(identifier)) [22264824](https://pubmed.ncbi.nlm.nih.gov/22264824).

1. **[^](#cite_ref-11)** Wang D, Garcia-Bassets I, Benner C, Li W, Su X, Zhou Y, et al. (May 2011). ["Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117022). *Nature*. **474** (7351): 390–394. [doi](/source/Doi_(identifier)):[10.1038/nature10006](https://doi.org/10.1038%2Fnature10006). [PMC](/source/PMC_(identifier)) [3117022](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117022). [PMID](/source/PMID_(identifier)) [21572438](https://pubmed.ncbi.nlm.nih.gov/21572438).

1. **[^](#cite_ref-pmid25678556_12-0)** Arner E, Daub CO, Vitting-Seerup K, Andersson R, Lilje B, Drabløs F, et al. (February 2015). ["Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681433). *Science*. **347** (6225): 1010–1014. [Bibcode](/source/Bibcode_(identifier)):[2015Sci...347.1010A](https://ui.adsabs.harvard.edu/abs/2015Sci...347.1010A). [doi](/source/Doi_(identifier)):[10.1126/science.1259418](https://doi.org/10.1126%2Fscience.1259418). [PMC](/source/PMC_(identifier)) [4681433](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681433). [PMID](/source/PMID_(identifier)) [25678556](https://pubmed.ncbi.nlm.nih.gov/25678556).

1. ^ [***a***](#cite_ref-Carullo_13-0) [***b***](#cite_ref-Carullo_13-1) Carullo NV, Phillips Iii RA, Simon RC, Soto SA, Hinds JE, Salisbury AJ, et al. (September 2020). ["Enhancer RNAs predict enhancer-gene regulatory links and are critical for enhancer function in neuronal systems"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515708). *Nucleic Acids Research*. **48** (17): 9550–9570. [doi](/source/Doi_(identifier)):[10.1093/nar/gkaa671](https://doi.org/10.1093%2Fnar%2Fgkaa671). [PMC](/source/PMC_(identifier)) [7515708](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515708). [PMID](/source/PMID_(identifier)) [32810208](https://pubmed.ncbi.nlm.nih.gov/32810208).

1. **[^](#cite_ref-pmid29378788_14-0)** Mikhaylichenko O, Bondarenko V, Harnett D, Schor IE, Males M, Viales RR, Furlong EE (January 2018). ["The degree of enhancer or promoter activity is reflected by the levels and directionality of eRNA transcription"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828394). *Genes & Development*. **32** (1): 42–57. [doi](/source/Doi_(identifier)):[10.1101/gad.308619.117](https://doi.org/10.1101%2Fgad.308619.117). [PMC](/source/PMC_(identifier)) [5828394](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828394). [PMID](/source/PMID_(identifier)) [29378788](https://pubmed.ncbi.nlm.nih.gov/29378788).

1. **[^](#cite_ref-pmid23417068_15-0)** Lai F, Orom UA, Cesaroni M, Beringer M, Taatjes DJ, Blobel GA, Shiekhattar R (February 2013). ["Activating RNAs associate with Mediator to enhance chromatin architecture and transcription"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109059). *Nature*. **494** (7438): 497–501. [Bibcode](/source/Bibcode_(identifier)):[2013Natur.494..497L](https://ui.adsabs.harvard.edu/abs/2013Natur.494..497L). [doi](/source/Doi_(identifier)):[10.1038/nature11884](https://doi.org/10.1038%2Fnature11884). [PMC](/source/PMC_(identifier)) [4109059](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109059). [PMID](/source/PMID_(identifier)) [23417068](https://pubmed.ncbi.nlm.nih.gov/23417068).

1. **[^](#cite_ref-pmid25693131_16-0)** Allen BL, Taatjes DJ (March 2015). ["The Mediator complex: a central integrator of transcription"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963239). *Nature Reviews. Molecular Cell Biology*. **16** (3): 155–166. [doi](/source/Doi_(identifier)):[10.1038/nrm3951](https://doi.org/10.1038%2Fnrm3951). [PMC](/source/PMC_(identifier)) [4963239](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963239). [PMID](/source/PMID_(identifier)) [25693131](https://pubmed.ncbi.nlm.nih.gov/25693131).

1. ^ [***a***](#cite_ref-pmid32514177_17-0) [***b***](#cite_ref-pmid32514177_17-1) Sartorelli V, Lauberth SM (June 2020). ["Enhancer RNAs are an important regulatory layer of the epigenome"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343394). *Nature Structural & Molecular Biology*. **27** (6): 521–528. [doi](/source/Doi_(identifier)):[10.1038/s41594-020-0446-0](https://doi.org/10.1038%2Fs41594-020-0446-0). [PMC](/source/PMC_(identifier)) [7343394](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343394). [PMID](/source/PMID_(identifier)) [32514177](https://pubmed.ncbi.nlm.nih.gov/32514177).

1. ^ [***a***](#cite_ref-pmid32888773_18-0) [***b***](#cite_ref-pmid32888773_18-1) Hou TY, Kraus WL (February 2021). ["Spirits in the Material World: Enhancer RNAs in Transcriptional Regulation"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855021). *Trends in Biochemical Sciences*. **46** (2): 138–153. [doi](/source/Doi_(identifier)):[10.1016/j.tibs.2020.08.007](https://doi.org/10.1016%2Fj.tibs.2020.08.007). [PMC](/source/PMC_(identifier)) [7855021](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855021). [PMID](/source/PMID_(identifier)) [32888773](https://pubmed.ncbi.nlm.nih.gov/32888773).

1. ^ [***a***](#cite_ref-pmid31993419_19-0) [***b***](#cite_ref-pmid31993419_19-1) Arnold PR, Wells AD, Li XC (2019). ["Diversity and Emerging Roles of Enhancer RNA in Regulation of Gene Expression and Cell Fate"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971116). *Frontiers in Cell and Developmental Biology*. **7** 377. [doi](/source/Doi_(identifier)):[10.3389/fcell.2019.00377](https://doi.org/10.3389%2Ffcell.2019.00377). [PMC](/source/PMC_(identifier)) [6971116](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971116). [PMID](/source/PMID_(identifier)) [31993419](https://pubmed.ncbi.nlm.nih.gov/31993419).

1. **[^](#cite_ref-pmid27068475_20-0)** Zhao Y, Wang L, Ren S, Wang L, Blackburn PR, McNulty MS, et al. (April 2016). ["Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395199). *Cell Reports*. **15** (3): 599–610. [doi](/source/Doi_(identifier)):[10.1016/j.celrep.2016.03.038](https://doi.org/10.1016%2Fj.celrep.2016.03.038). [PMC](/source/PMC_(identifier)) [5395199](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395199). [PMID](/source/PMID_(identifier)) [27068475](https://pubmed.ncbi.nlm.nih.gov/27068475).

1. **[^](#cite_ref-pmid25263592_21-0)** Schaukowitch K, Joo JY, Liu X, Watts JK, Martinez C, Kim TK (October 2014). ["Enhancer RNA facilitates NELF release from immediate early genes"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186258). *Molecular Cell*. **56** (1): 29–42. [doi](/source/Doi_(identifier)):[10.1016/j.molcel.2014.08.023](https://doi.org/10.1016%2Fj.molcel.2014.08.023). [PMC](/source/PMC_(identifier)) [4186258](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186258). [PMID](/source/PMID_(identifier)) [25263592](https://pubmed.ncbi.nlm.nih.gov/25263592).

1. ^ [***a***](#cite_ref-Wyers2005_22-0) [***b***](#cite_ref-Wyers2005_22-1) Wyers F, Rougemaille M, Badis G, Rousselle JC, Dufour ME, Boulay J, et al. (June 2005). ["Cryptic pol II transcripts are degraded by a nuclear quality control pathway involving a new poly(A) polymerase"](https://doi.org/10.1016%2Fj.cell.2005.04.030). *Cell*. **121** (5): 725–737. [doi](/source/Doi_(identifier)):[10.1016/j.cell.2005.04.030](https://doi.org/10.1016%2Fj.cell.2005.04.030). [PMID](/source/PMID_(identifier)) [15935759](https://pubmed.ncbi.nlm.nih.gov/15935759).

1. **[^](#cite_ref-23)** Ren B (May 2010). ["Transcription: Enhancers make non-coding RNA"](https://doi.org/10.1038%2F465173a). *Nature*. **465** (7295): 173–174. [Bibcode](/source/Bibcode_(identifier)):[2010Natur.465..173R](https://ui.adsabs.harvard.edu/abs/2010Natur.465..173R). [doi](/source/Doi_(identifier)):[10.1038/465173a](https://doi.org/10.1038%2F465173a). [PMID](/source/PMID_(identifier)) [20463730](https://pubmed.ncbi.nlm.nih.gov/20463730).

1. **[^](#cite_ref-24)** Obrdlik A, Kukalev A, Louvet E, Farrants AK, Caputo L, Percipalle P (October 2008). ["The histone acetyltransferase PCAF associates with actin and hnRNP U for RNA polymerase II transcription"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577438). *Molecular and Cellular Biology*. **28** (20): 6342–6357. [doi](/source/Doi_(identifier)):[10.1128/MCB.00766-08](https://doi.org/10.1128%2FMCB.00766-08). [PMC](/source/PMC_(identifier)) [2577438](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577438). [PMID](/source/PMID_(identifier)) [18710935](https://pubmed.ncbi.nlm.nih.gov/18710935).

1. **[^](#cite_ref-25)** Feng J, Bi C, Clark BS, Mady R, Shah P, Kohtz JD (June 2006). ["The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1475760). *Genes & Development*. **20** (11): 1470–1484. [doi](/source/Doi_(identifier)):[10.1101/gad.1416106](https://doi.org/10.1101%2Fgad.1416106). [PMC](/source/PMC_(identifier)) [1475760](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1475760). [PMID](/source/PMID_(identifier)) [16705037](https://pubmed.ncbi.nlm.nih.gov/16705037).

1. **[^](#cite_ref-Wang2009_26-0)** Wang Z, Gerstein M, Snyder M (January 2009). ["RNA-Seq: a revolutionary tool for transcriptomics"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949280). *Nature Reviews. Genetics*. **10** (1): 57–63. [doi](/source/Doi_(identifier)):[10.1038/nrg2484](https://doi.org/10.1038%2Fnrg2484). [PMC](/source/PMC_(identifier)) [2949280](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949280). [PMID](/source/PMID_(identifier)) [19015660](https://pubmed.ncbi.nlm.nih.gov/19015660).

1. ^ [***a***](#cite_ref-Barski2007_27-0) [***b***](#cite_ref-Barski2007_27-1) Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, et al. (May 2007). ["High-resolution profiling of histone methylations in the human genome"](https://doi.org/10.1016%2Fj.cell.2007.05.009). *Cell*. **129** (4): 823–837. [doi](/source/Doi_(identifier)):[10.1016/j.cell.2007.05.009](https://doi.org/10.1016%2Fj.cell.2007.05.009). [PMID](/source/PMID_(identifier)) [17512414](https://pubmed.ncbi.nlm.nih.gov/17512414).

1. **[^](#cite_ref-28)** Melgar MF, Collins FS, Sethupathy P (November 2011). ["Discovery of active enhancers through bidirectional expression of short transcripts"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334599). *Genome Biology*. **12** (11) R113. [doi](/source/Doi_(identifier)):[10.1186/gb-2011-12-11-r113](https://doi.org/10.1186%2Fgb-2011-12-11-r113). [PMC](/source/PMC_(identifier)) [3334599](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334599). [PMID](/source/PMID_(identifier)) [22082242](https://pubmed.ncbi.nlm.nih.gov/22082242).

1. **[^](#cite_ref-29)** Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, et al. (December 2010). ["Histone H3K27ac separates active from poised enhancers and predicts developmental state"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003124). *Proceedings of the National Academy of Sciences of the United States of America*. **107** (50): 21931–21936. [doi](/source/Doi_(identifier)):[10.1073/pnas.1016071107](https://doi.org/10.1073%2Fpnas.1016071107). [PMC](/source/PMC_(identifier)) [3003124](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003124). [PMID](/source/PMID_(identifier)) [21106759](https://pubmed.ncbi.nlm.nih.gov/21106759).

1. **[^](#cite_ref-30)** Yao L, Liang J, Ozer A, Leung AK, Lis JT, Yu H (July 2022). ["A comparison of experimental assays and analytical methods for genome-wide identification of active enhancers"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9288987). *Nature Biotechnology*. **40** (7): 1056–1065. [doi](/source/Doi_(identifier)):[10.1038/s41587-022-01211-7](https://doi.org/10.1038%2Fs41587-022-01211-7). [PMC](/source/PMC_(identifier)) [9288987](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9288987). [PMID](/source/PMID_(identifier)) [35177836](https://pubmed.ncbi.nlm.nih.gov/35177836).

1. **[^](#cite_ref-31)** Mahat DB, Kwak H, Booth GT, Jonkers IH, Danko CG, Patel RK, et al. (August 2016). ["Base-pair-resolution genome-wide mapping of active RNA polymerases using precision nuclear run-on (PRO-seq)"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502525). *Nature Protocols*. **11** (8): 1455–1476. [doi](/source/Doi_(identifier)):[10.1038/nprot.2016.086](https://doi.org/10.1038%2Fnprot.2016.086). [PMC](/source/PMC_(identifier)) [5502525](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502525). [PMID](/source/PMID_(identifier)) [27442863](https://pubmed.ncbi.nlm.nih.gov/27442863).

1. **[^](#cite_ref-32)** Melo CA, Drost J, Wijchers PJ, van de Werken H, de Wit E, Oude Vrielink JA, et al. (February 2013). ["eRNAs are required for p53-dependent enhancer activity and gene transcription"](https://doi.org/10.1016%2Fj.molcel.2012.11.021). *Molecular Cell*. **49** (3): 524–535. [doi](/source/Doi_(identifier)):[10.1016/j.molcel.2012.11.021](https://doi.org/10.1016%2Fj.molcel.2012.11.021). [PMID](/source/PMID_(identifier)) [23273978](https://pubmed.ncbi.nlm.nih.gov/23273978).

1. **[^](#cite_ref-33)** Vousden KH, Lu X (August 2002). ["Live or let die: the cell's response to p53"](https://zenodo.org/record/1233502). *Nature Reviews. Cancer*. **2** (8): 594–604. [doi](/source/Doi_(identifier)):[10.1038/nrc864](https://doi.org/10.1038%2Fnrc864). [PMID](/source/PMID_(identifier)) [12154352](https://pubmed.ncbi.nlm.nih.gov/12154352). [S2CID](/source/S2CID_(identifier)) [6412605](https://api.semanticscholar.org/CorpusID:6412605).

1. **[^](#cite_ref-34)** Zhang, Troy; Yu, Hui; Jiang, Limin; Bai, Yongsheng; Liu, Xiaoyi; Guo, Yan (January 2024). ["Comprehensive Pan-Cancer Mutation Density Patterns in Enhancer RNA"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10778997). *International Journal of Molecular Sciences*. **25** (1): 534. [doi](/source/Doi_(identifier)):[10.3390/ijms25010534](https://doi.org/10.3390%2Fijms25010534). [ISSN](/source/ISSN_(identifier)) [1422-0067](https://search.worldcat.org/issn/1422-0067). [PMC](/source/PMC_(identifier)) [10778997](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10778997). [PMID](/source/PMID_(identifier)) [38203707](https://pubmed.ncbi.nlm.nih.gov/38203707).

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## External links

- [Vista Enhancer Database](http://enhancer.lbl.gov/)

- [Mouse ENCODE Project](http://chromosome.sdsc.edu/mouse/download.html) [Archived](https://web.archive.org/web/20121213045104/http://chromosome.sdsc.edu/mouse/download.html) 2012-12-13 at the [Wayback Machine](/source/Wayback_Machine)

- [ENCODE Project at UCSC](https://archive.today/20121209133547/http://encodeproject.org/ENCODE/)

- [PEDB](https://web.archive.org/web/20121115182532/http://promoter.cdb.riken.jp/)

v t e Types of nucleic acids Constituents Nucleobases Nucleosides Nucleotides Deoxynucleotides Ribonucleic acids (coding, non-coding) Translational Messenger precursor, heterogenous nuclear modified Messenger Transfer Ribosomal Transfer-messenger Regulatory Interferential Micro Small interfering Piwi-interacting Antisense Processual Small nuclear Small nucleolar Small Cajal Body RNAs Y RNA Enhancer RNAs Others Guide Ribozyme Short hairpin Small temporal Trans-acting small interfering Subgenomic messenger Deoxyribonucleic acids Organellar Chloroplast Mitochondrial Complementary Deoxyribozyme Genomic Hachimoji Multicopy single-stranded Analogues Xeno Glycol Threose Hexose Locked Peptide Morpholino Phosphorothioate Cloning vectors Phagemid Plasmid Lambda phage Cosmid Fosmid Artificial chromosomes P1-derived Bacterial Yeast Human Category

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Adapted from the Wikipedia article [Enhancer RNA](https://en.wikipedia.org/wiki/Enhancer_RNA) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Enhancer_RNA?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.