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

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RNA Epigenetics: Fine-Tuning Chromatin Plasticity and Transcriptional Regulation, and the Implications in Human Diseases G C A T T A C G G C A T genes Review RNA Epigenetics: Fine-Tuning Chromatin Plasticity and Transcriptional Regulation, and the Implications in Human Diseases Amber Willbanks, Shaun Wood and Jason X. Cheng * Department of Pathology, Hematopathology Section, University of Chicago, Chicago, IL 60637, USA; [email protected] (A.W.); [email protected] (S.W.) * Correspondence: [email protected] 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: 5’ cap (5’ cap); 7-methylguanosine (m7G); R-loops; N6-methyladenosine (m6A); RNA editing; A-to-I; C-to-U; 2’-O-methylation (Nm); 5-methylcytosine (m5C); NOL1/NOP2/sun domain Citation: Willbanks, A.; Wood, S.; (NSUN); MYC Cheng, J.X. RNA Epigenetics: Fine-Tuning Chromatin Plasticity and Transcriptional Regulation, and the Implications in Human Diseases. Genes 2021, 12, 627. https://doi.org/ 1. Introduction 10.3390/genes12050627 In eukaryotes, genomic DNA and its associated proteins, primarily histones, are or- ganized into chromatin structural domains that affect the binding of transcription factors Academic Editor: Vincenzo Cavalieri (TFs), recruitment of RNA polymerases (RNAPs) and the initiation and elongation of transcription [1]. The advent of new genome-wide sequencing technologies has identified Received: 1 March 2021 chromatin-associated RNAs (ChrRNAs) [2], including nascent RNAs, coding RNAs and Accepted: 14 April 2021 various regulatory non-coding RNAs (ncRNAs). RNAs can act either in cis by targeting Published: 22 April 2021 genomic DNA or in trans through RNAP complexes and interactions with DNA-binding proteins, such as TFs and DNA/histone modifiers, to regulate chromatin structure and Publisher’s Note: MDPI stays neutral gene expression. There are extensive studies and reviews of the roles of ncRNAs in the with regard to jurisdictional claims in regulation of DNA/histone modifications, chromatin structure, and gene expression [3–10]. published maps and institutional affil- In contrast, the role of RNA modifications and RNA modifying proteins (RMPs) in chro- iations. matin plasticity and transcription regulation remains largely unknown. This review will discuss recent studies, which suggest RNA modifications and RMPs function to fine-tune chromatin structure, in turn facilitating transcription activation or repression. Copyright: © 2021 by the authors. 2. Co- and Post-Transcriptional RNA Modifications and RNA Modifying Proteins Licensee MDPI, Basel, Switzerland. 2.1. Overview of RNA Modifications and RMPs This article is an open access article Over 170 chemical modifications have been identified in RNA [11]. The associated distributed under the terms and RNA modifying proteins (RMPs) are classified into three groups based on their roles in RNA conditions of the Creative Commons modification: (1) writers: enzymes that catalyze specific RNA modifications, (2) readers: Attribution (CC BY) license (https:// enzymes that recognize and selectively bind to RNA modifications and (3) erasers: enzymes creativecommons.org/licenses/by/ 4.0/). that remove specific RNA modifications. These RMPs are distributed throughout the Genes 2021, 12, 627. https://doi.org/10.3390/genes12050627 https://www.mdpi.com/journal/genes Genes 2021, 12, x FOR PEER REVIEW 2 of 41 RNA modifying proteins (RMPs) are classified into three groups based on their roles in Genes 2021, 12, 627 RNA modification: (1) writers: enzymes that catalyze specific RNA modifications,2 of 41 (2) readers: enzymes that recognize and selectively bind to RNA modifications and (3) erasers: enzymes that remove specific RNA modifications. These RMPs are distributed throughout the nuclei, cytoplasm and mitochondria and are involved in nearly all essen- nuclei, cytoplasm and mitochondria and are involved in nearly all essential bioprocesses tial(Figure bioprocesses1) [11–13 (Figure]. In this 1) section, [11–13]. we In will this provide section, a we brief will update provide on the a brief common update RNA on the commonmodifications RNA andmodifications their associated and RMPstheir asassociated well as their RMPs impact as on well chromatin as their structure impact on chromatinand transcription structure regulation. and transcription The common regu RNAlation. modifications The common and theirRNA writers, modifications readers and theirand writers, erasers arereaders shown and inFigures erasers2 andare3 ;show N6-methyladenosinen in Figures 2 (mand6 A)3; andN6-methyladenosine its RMPs are 5 (msummarized6A) and its RMPs in Figure are2 A;summarized 5-methylcytosine in Figure (m C) 2A; and 5-methylcytosine its RMPs in Figure (m2B;5C) Adenosine and its RMPs in Figureto inosine 2B; (A-to-I) Adenosine RNA editingto inosine and its(A-to-I) RMPs inRNA Figure editing3A; Cytosine and its to RMPs uracil in RNA Figure editing 3A; Cy- tosineand to its uracil RMPs inRNA Figure editing3B. and its RMPs in Figure 3B. FigureFigure 1. Subcellular 1. Subcellular Distribution Distribution of ofRNA RNA Mo Modificationsdifications and RMPsRMPs in in Eukaryotes. Eukaryotes Abbreviations:. Abbreviations: RMP, RMP, RNA RNA modifying modifying 7 6 5 protein;protein; RBP, RBP, RNA RNA binding binding proteins; proteins; m mG,7G, 7-methylguanosine; 7-methylguanosine; Nm, Nm, 2 02-O-methylation;′-O-methylation; m6 A,m N6-methyladenosine;A, N6-methyladenosine; m5C, m C, 5-methylcytosine;5-methylcytosine; hnRNPs, hnRNPs, heteroge heterogeneousneous nuclear nuclear ribonucleoproteins. ribonucleoproteins. GenesGenes 2021,2021 12, ,x12 FOR, 627 PEER REVIEW 3 of 413 of 41 Figure 2. Formation, Recognition and Removal of RNA m6A and m5C in Eukaryotes. (A). Formation, Recognition and 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 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 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 removed by RNA m6A erasers. (B). Formation, Recognition and Removal of RNA:m5C. RNA m5C writers methylate cy- cytosine residues, which are then recognized by m5C readers, or TETs, which oxidize m5C to hm5C, f5C and ca5C, tosine residues, which are then recognized by m5C readers, or TETs, which oxidize m5C to hm5C, f5C and ca5C, respec- tively.respectively. Abbreviations: Abbreviations: SAM, S-adenosyl SAM, S-adenosylmethionine;methionine; SAH, S-adenos SAH, S-adenosylyl homocysteine; homocysteine; RBM15, RBM15, RNA RNA binding binding motif motif protein 15; METTL3/14,protein 15; METTL3/14, methyltransferase methyltransferase like 3/14; like ZC3H13, 3/14; ZC3H13, zinc finger zinc finger CCCH-type CCCH-type containing containing 13; 13; WTAP, WTAP, Wilms tumortumor sup- pressorsuppressor gene WT1; gene WT1;VIRMA, VIRMA, Vir-like Vir-like m6A m6A methyltransferase methyltransferase associat associated;ed; HAKAI,HAKAI, Cbl Cbl Proto-Oncogene Proto-Oncogene Like Like 1; FTO, 1; FatFTO, Fat massmass and andobesity obesity associated; associated; ALKBH5, ALKBH5, AlkB homologhomolog 5; 5; YTHDC1/2, YTHDC1/2, YTH YTH domain domain containing containing 1/2; YTHDF2/3,1/2; YTHDF2/3, YTH N6,YTH N6, methyladenosinemethyladenosine RNA-binding RNA-binding protein protein 2/3; HNRNP family,family, heterogeneous heterogeneous nuclear nuclear ribonucleoproteins; ribonucleoproteins; IGF2BP1/2/3, IGF2BP1/2/3, insulin-likeinsulin-like growth growth factor factor 2 mRNA 2 mRNA binding binding protein protein 1/2/ 1/2/3.3. NSUN NSUN family, family, NOL1/NOP2/sun domain; DNMT2,DNMT2, DNA DNA me- thyltransferasemethyltransferase 2; ALYREF, 2; ALYREF, Aly/REF Aly/REF export export factor; factor; YTHDF2, YTHDF2, YTH YTH N6-methyladenosine N6-methyladenosine RNA bindingbinding protein protein 2; 2; TETs, TETs, ten 5 5 5 eleventen translocation eleven translocation elements; elements; hm5C, hm 5-hydroxymethylcytosine;C, 5-hydroxymethylcytosine; f5C, f C, 5-formylcytosine; 5-formylcytosine; ca 5C, 5-carboxylcytosine. Genes 2021, 12, x FOR PEER REVIEW 4 of 41 Genes 2021, 12, 627 4 of 41 Figure 3. Molecular Reactions of RNA Adenosine to Inosine (A-to-I) and Cytidine to Uridine (C-to-U) Editing in Eukaryotes. Figure(A 3.). A-to-IMolecular RNA Reactions Editing Mechanism. of RNA ADAR1Adenosine and to ADAR2 Inosine catalyze (A-to-I) the site-specificand Cytidine
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