Non-coding RNAs as regulators of gene expression and epigenetics - PubMed (original) (raw)

Review

. 2011 Jun 1;90(3):430-40.

doi: 10.1093/cvr/cvr097. Epub 2011 May 9.

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Review

Non-coding RNAs as regulators of gene expression and epigenetics

Minna U Kaikkonen et al. Cardiovasc Res. 2011.

Abstract

Genome-wide studies have revealed that mammalian genomes are pervasively transcribed. This has led to the identification and isolation of novel classes of non-coding RNAs (ncRNAs) that influence gene expression by a variety of mechanisms. Here we review the characteristics and functions of regulatory ncRNAs in chromatin remodelling and at multiple levels of transcriptional and post-transcriptional regulation. We also describe the potential roles of ncRNAs in vascular biology and in mediating epigenetic modifications that might play roles in cardiovascular disease susceptibility. The emerging recognition of the diverse functions of ncRNAs in regulation of gene expression suggests that they may represent new targets for therapeutic intervention.

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Figures

Figure 1

Figure 1

Potential promoter-associated RNAs and enhancer RNAs produced upstream of (A) fibroblast growth factor 2 (FGF-2) and (B) vascular endothelial growth factor C (VEGF-C) genes in human IMR90 cells. The promoter-associated RNAs (highlighted in red) colocalize with H3K4me3 histone mark, whereas the eRNAs (highlighted in blue) are revealed by their overlap with H3K4me1 mark. Regions upstream of transcription start site (TSS) for FGF-2 and VEGF-C are 50 and 100 kb, respectively. The _y_-axis indicates the number of sequencing tags.

Figure 2

Figure 2

Mechanisms for regulation of epigenetics and gene expression by non-coding RNAs. NcRNAs can function as modulators of epigenetics through (A through C) chromatin remodelling or regulate gene expression at (D through F) transcriptional or (G through I) post-transcriptional level. (A) A 5′ domain of HOTAIR binds polycomb repressive complex 2 (PRC2), whereas a 3′ domain of HOTAIR binds the LSD1/CoREST/REST complex. This allows HOTAIR to coordinate histone H3 lysine 27 methylation and lysine 4 demethylation at the HOXD locus in trans. (B) In cis recruitment of PRC2 by Xist antisense RNA and appearance of H3K27me3 along the inactive X chromosome are among the earliest events in X inactivation. Recruitment of PRC1-mediated H2AK119ub1 parallels the recruitment of PRC2. (C) Similarly, antisense non-coding RNA ANRIL represses the expression from INK4b/ARF/INK4a locus by recruiting and retaining PRC1 and PRC2 complexes in cis. (D) LncRNA transcribed from the minor promoter of dihydrofolate reductase (DHFR) froms a triplex together with the transcription factor TFIIB and the major promoter leading to the dissociation of the preinitiation complex. (E) Enhancer region (i and ii) of Dlx5/6 generates an lncRNA Evf-2 which forms a complex with homeodomain protein Dlx-2 to activate transcription. (F) Transcription of B2 and Alu RNAs is induced upon heat-shock. They inhibit mRNA synthesis by disrupting contacts between RNA polymerase II and promoter DNA. (G) Small interfering RNAs (siRNAs) and microRNAs (miRNAs) are incorporated into RNA-induced silencing complexes (RISCs) that target specific mRNAs for cleavage, translational repression or destabilization depending on the extent of sequence complementarity. (H) Natural antisense transcript (NAT) prevents the binding of the spliceosome to the 5′UTR of the Zeb2 mRNA. This leads to retention in an intron containing internal ribosomal entry site (IRES), which is dispensable for the translation of Zeb2 protein. (I) The nuclear trafficking of nuclear factor of activated T cells (NFAT) is inhibited by the interaction of non-coding repressor of NFAT (NRON) with proteins of the importin-beta superfamily.

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