Enhancer RNA

Source: Wikipedia, the free encyclopedia.
"ERNA" redirects here. For other uses, see ERNA (disambiguation).

Enhancer RNAs (eRNAs) represent a class of relatively long

cis and in trans, and while their mechanisms of action remain unclear, a few models have been proposed.[3]

Discovery

molecules.[1]

Biogenesis

eRNA Biogenesis

Summary

eRNAs are transcribed from

sequences.[2][1]

Depending on the directionality of

enhancers greatly outnumbering the transcribed ones in the order of magnitude of dozens of thousands in every given cell type.[5]

1D eRNAs

In most cases, unidirectional

enhancers. These long non-coding RNAs, which accurately reflect the host gene's structure except for the alternative first 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

gene transcription.[11]

Frequency and timing of eRNA expression

Arner et al.[12] identified 65,423 transcribed 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 which, in turn, generally preceded messenger RNA(mRNA) transcription of genes.

Carullo et al.

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 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
(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 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

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

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 (see Figure), especially Mediator subunit 12 (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. High PSA eRNA then has a domino effect. PSA eRNA binds to and activates the positive transcription elongation factor P-TEFb protein complex which can then phosphorylate RNA polymerase II (RNAP II), initiating its activity in producing mRNA. P-TEFb can also phosphorylate the 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 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 (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

experimental evidence
.

Transcriptional Noise

Since multiple studies have shown that

extragenic transcriptional noise at sites where 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

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

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

cis
, 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

enhancers
.

Implications in development and disease

Evidence that eRNAs cause downstream effects on the efficiency of enhancer activation and gene transcription suggests its functional capabilities and potential importance. The

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

RNAi
may provide promising routes to target disruption of gene expression.

References

  1. ^
    PMID 20393465
    .
  2. ^
    PMID 20485488
    .
  3. ^
    PMID 22905871
    .
  4. ^
    PMID 28870212
    .
  5. ^
    PMID 20485488
    .
  6. S2CID 1595885
    .
  7. ^
    S2CID 12778976
    .
  8. S2CID 14304312
    .
  9. ^
    PMID 18509338
    .
  10. PMID 22264824
    .
  11. PMID 21572438
    .
  12. PMID 25678556
    .
  13. ^
    PMID 32810208
    .
  14. PMID 29378788
    .
  15. PMID 23417068
    .
  16. PMID 25693131
    .
  17. ^
    PMID 32514177
    .
  18. ^
    PMID 32888773
    .
  19. ^
    PMID 31993419
    .
  20. PMID 27068475
    .
  21. PMID 25263592
    .
  22. ^
    PMID 15935759
    .
  23. PMID 20463730
    .
  24. PMID 18710935
    .
  25. PMID 16705037
    .
  26. PMID 19015660
    .
  27. ^
    PMID 17512414
    .
  28. PMID 22082242
    .
  29. PMID 21106759
    .
  30. PMID 35177836
    .
  31. PMID 27442863
    .
  32. PMID 23273978
    .
  33. S2CID 6412605
    .
  34. PMID 38203707
    .

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Enhancer_RNA&oldid=1213305466"