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Review
. 2021 Apr 22;12(5):627.
doi: 10.3390/genes12050627.

RNA Epigenetics: Fine-Tuning Chromatin Plasticity and Transcriptional Regulation, and the Implications in Human Diseases

Amber Willbanks  1 , Shaun Wood  1 , Jason X Cheng  1
Affiliations
Review

RNA Epigenetics: Fine-Tuning Chromatin Plasticity and Transcriptional Regulation, and the Implications in Human Diseases

Amber Willbanks et al. Genes (Basel). .

Abstract

Chromatin structure plays an essential role in eukaryotic gene expression and cell identity. Traditionally, DNA and histone modifications have been the focus of chromatin regulation; however, recent molecular and imaging studies have revealed an intimate connection between RNA epigenetics and chromatin structure. Accumulating evidence suggests that RNA serves as the interplay between chromatin and the transcription and splicing machineries within the cell. Additionally, epigenetic modifications of nascent RNAs fine-tune these interactions to regulate gene expression at the co- and post-transcriptional levels in normal cell development and human diseases. This review will provide an overview of recent advances in the emerging field of RNA epigenetics, specifically the role of RNA modifications and RNA modifying proteins in chromatin remodeling, transcription activation and RNA processing, as well as translational implications in human diseases.

Keywords: 2’-O-methylation (Nm); 5-methylcytosine (m5C); 5’ cap (5’ cap); 7-methylguanosine (m7G); A-to-I; C-to-U; MYC; N6-methyladenosine (m6A); NOL1/NOP2/sun domain (NSUN); R-loops; RNA editing.

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Conflict of interest statement

No conflicts of interest declared by the authors.

Figures

Figure 1
Figure 1
Subcellular Distribution of RNA Modifications and RMPs in Eukaryotes. Abbreviations: RMP, RNA modifying protein; RBP, RNA binding proteins; m7G, 7-methylguanosine; Nm, 2′-O-methylation; m6A, N6-methyladenosine; m5C, 5-methylcytosine; hnRNPs, heterogeneous nuclear ribonucleoproteins.
Figure 2
Figure 2
Formation, Recognition and Removal of RNA m6A and m5C in Eukaryotes. (A). Formation, Recognition and Removal of RNA:m6A. The METTL3/14 methyltransferase complex transfers methyl groups from SAM to N6-adenosines at the RRAH motifs in RNA. m6A is then recognized by m6A readers (m6A-selective binding proteins), and eventually removed by RNA m6A erasers. (B). Formation, Recognition and Removal of RNA:m5C. RNA m5C writers methylate cytosine residues, which are then recognized by m5C readers, or TETs, which oxidize m5C to hm5C, f5C and ca5C, respectively. Abbreviations: SAM, S-adenosylmethionine; SAH, S-adenosyl homocysteine; RBM15, RNA binding motif protein 15; METTL3/14, methyltransferase like 3/14; ZC3H13, zinc finger CCCH-type containing 13; WTAP, Wilms tumor suppressor gene WT1; VIRMA, Vir-like m6A methyltransferase associated; HAKAI, Cbl Proto-Oncogene Like 1; FTO, Fat mass and obesity associated; ALKBH5, AlkB homolog 5; YTHDC1/2, YTH domain containing 1/2; YTHDF2/3, YTH N6, methyladenosine RNA-binding protein 2/3; HNRNP family, heterogeneous nuclear ribonucleoproteins; IGF2BP1/2/3, insulin-like growth factor 2 mRNA binding protein 1/2/3. NSUN family, NOL1/NOP2/sun domain; DNMT2, DNA methyltransferase 2; ALYREF, Aly/REF export factor; YTHDF2, YTH N6-methyladenosine RNA binding protein 2; TETs, ten eleven translocation elements; hm5C, 5-hydroxymethylcytosine; f5C, 5-formylcytosine; ca5C, 5-carboxylcytosine.
Figure 3
Figure 3
Molecular Reactions of RNA Adenosine to Inosine (A-to-I) and Cytidine to Uridine (C-to-U) Editing in Eukaryotes. (A). A-to-I RNA Editing Mechanism. ADAR1 and ADAR2 catalyze the site-specific conversion of A-to-I within imperfectly duplexed RNA. Meanwhile ADAR3 inhibits A-to-I editing. (B). C-to-U RNA Editing Mechanism. APOBEC1 and ACF bind to the RNA duplex, and RBM47 interacts with APOBEC1 and ACF, to produce C-to-U conversion via hydrolytic deamination of cytidine. Abbreviations: ADAR1/2, adenosine deaminases acting on RNA; APOBEC1, apolipoprotein B mRNA editing enzyme catalytic subunit 1; RBM47, RNA binding motif protein 47; ACF/A1CF, APOBEC1-complementation factor.
Figure 4
Figure 4
5′ Cap Structure of a Human Pre-mRNA and the Associated Methylations and Methyltransferase Complexes. Abbreviations: m7G, 7-methylguanosine; RGMT, RNA guanine methyltransferase; RNGTT, RNA guanylyltransferase and 5′ phosphatase; RTPase-RNA triphosphatase; SAM, S-adenosylmethionine; SAH, S-adenosyl homocysteine; PCIF1/CAPAM, PDX C-terminal inhibiting factor 1; CMTR1/2, cap methyltransferase 1/2.
Figure 5
Figure 5
Transcriptionally Active Chromatin Structure and the Five Steps of Transcription Activation. Step 1. Chromatin remodeling; Step 2. Formation of transcription pre-initiation complex (PIC); Step 3. Unwinding of the DNA strands to form the open complex; Step 4. RNA polymerase II (RNAPII) pausing and escaping from the promoter; Step 5. Productive transcript elongation by RNAPII. Abbreviations: SWI-SNF, switch/Sucrose non-fermentable; TF, transcription factor; H, histone; PIC, preinitiation complex; GTFs, general transcription factors; TFIIA-F, transcription factor II A–F; TAF1, TATA-box binding protein associated factor 1; TBP, TATA-box binding protein; CDK7/TFIIH, cyclin-dependent kinase 7; TSS, transcription start Site; Spt5/4, suppressor of Ty 5 and 4 (transcription elongation factors 5 and 4); DSIF, DRB sensitivity-inducing factor; CDK9/p-TEFb, cyclin-dependent kinase 9.
Figure 6
Figure 6
MYC-mediated RNA 5′ Capping, Transcription Elongation and Chromatin Structure. Abbreviations: E-box- enhancer box; MYC- MYC proto-oncogene BHLH transcription factor; RNMT, RNA methyltransferase; CMTR1, cap methyltransferase 1; K-ac, acetylated lysine; CDK9/P-TEFb, cyclin-dependent Kinase 9; CDK7/TFIIH, Cyclin-dependent Kinase 7; BRD4, Bromodomain Containing 4; 7SK snRNP, 7SK small nuclear ribonucleoprotein.
Figure 7
Figure 7
Transcription-associated Spliceosome Assembly and Alternative Splicing in Eukaryotes. (A). Determination of the first exon-intron boundary and formation of initial spliceosome on pre-mRNA. (B). Transcription-associated determination of the internal exon-intron boundaries, spliceosome assembly and alternative splicing of pre-mRNA. Abbreviations: CTCF, CCCTC binding protein; MeCP2, methyl-CpG binding protein 2; DNMT, DNA methyltransferase; TET, ten eleven translocation elements; E-box, enhancer box; CE/RNGTT, RNA guanylyltransferase and 5′-Phosphatase; HMT, histone methyltransferase; HAT, histone acetyltransferase; BRD4, bromodomain containing 4; U1-U6, small nuclear ribonucleoprotein U1-U6 subunit; CDK9/P-TEFb, cyclin-dependent kinase 9; 7SK snRNP, 7SK small nuclear ribonucleoprotein; SF3A/B, splicing factor 3a/b subunit; CDK7/TFIIH, cyclin-dependent kinase 7; TETs, ten eleven translocation elements; SRSF, serine/arginine-rich splicing factors; hnRNP, heterogeneous nuclear ribonucleoproteins; RBP, RNA binding proteins.
Figure 8
Figure 8
RNA Modification/RMP-mediated, Transcription-associated Chromatin Structural Changes in Mammalian Cells. (A). m6A and its RMPs-mediated chromatin structural changes. (B). m5C and its RMPs-mediated chromatin structural changes. Abbreviations: m6A, N6-methyladenine; RNMT, RNA Methyltransferase; CMTR1, cap methyltransferase 1; KDM3B, lysine demethylase 3B; YTHDC1, YTH Domain Containing 1; EZH2, enhancer of Zeste 2 Polycomb repressive Complex 2 Subunit; METTL3/14, methyltransferase Like 3/14; K9me, lysine 9 methyl; K27me, lysine 27 methyl; TFs, Transcription Factors; ZFP217, zinc finger Protein 217; H3K4me36, histone 3 lysine 36 tri-methylation; E-box, enhancer box; CDK9/P-TEFb, cyclin-dependent kinase 9; CDK7/TFIIH, cyclin-dependent kinase 7. m5C, 5-methylcytosine; MeCP2, methyl-CpG binding protein 2; SET7/9, SET Domain containing 7/9 histone lysine methyltransferase; SAGA, Spt-Ada-Gcn5-acetyltransferase; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1-α; NSUN7, NOP2/Sun RNA methyltransferase member 7; H3K4me36, histone 3 lysine 36 tri-methylation; NOP2/NSUN1, NOP2 nucleolar protein/NOP2/Sun RNA methyltransferase 1; K-ac, lysine acetylation; BRD5/BET, bromodomain containing 4; E-box, enhancer box; CDK9/pTEFb, cyclin-dependent kinase 9; CDK7/TFIIH, cyclin-dependent Kinase 7; MYC, MYC proto-oncogene BHLH transcription factor.
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