Crosstalk between epitranscriptomic and epigenetic mechanisms in gene regulation - PubMed (original) (raw)

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Crosstalk between epitranscriptomic and epigenetic mechanisms in gene regulation

Ryan L Kan et al. Trends Genet. 2022 Feb.

Abstract

Epigenetic modifications occur on genomic DNA and histones to influence gene expression. More recently, the discovery that mRNA undergoes similar chemical modifications that powerfully impact transcript turnover and translation adds another layer of dynamic gene regulation. Central to precise and synchronized regulation of gene expression is intricate crosstalk between multiple checkpoints involved in transcript biosynthesis and processing. There are more than 100 internal modifications of RNA in mammalian cells. The most common is N6-methyladenosine (m6A) methylation. Although m6A is established to influence RNA stability dynamics and translation efficiency, rapidly accumulating evidence shows significant crosstalk between RNA methylation and histone/DNA epigenetic mechanisms. These interactions specify transcriptional outputs, translation, recruitment of chromatin modifiers, as well as the deployment of the m6A methyltransferase complex (MTC) at target sites. In this review, we dissect m6A-orchestrated feedback circuits that regulate histone modifications and the activity of regulatory RNAs, such as long noncoding (lnc)RNA and chromosome-associated regulatory RNA. Collectively, this body of evidence suggests that m6A acts as a versatile checkpoint that can couple different layers of gene regulation with one another.

Keywords: RNA methylation; RNA modification; epigenetics; gene regulation.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

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Conflict of interest statement

Declaration of interests J.C. is a scientific advisor for Race Oncology and a scientific founder of Genovel Biotech Corp., in which he also holds equities.

Figures

Figure 3.

Figure 3.

Chromosome-associated regulatory RNAs (carRNAs) or mRNA that encode histone-modifying enzymes are methylated and tagged for degradation, causing a decrease in carRNA and histone acetyltransferases (HATs) or histone methyltransferases (HMTs), ultimately leading to accessible chromatin. KDM3B is shown as a representative enzyme that is recruited by m6A. Other histone-modifying factors, such as Setdb1 and Trim28, are recruited in the same fashion. RBM15/RBM15B-mediated m6A deposition and subsequent YTHDC1 recruitment are essential for X-chromosome silencing.

Figure 1.

Figure 1.. Schematic of epigenetic and epitranscriptomic mechanisms.

Modifications of DNA or histone proteins alter RNA polymerase II (RNA Pol II) transcriptional output. Chemical modifications on RNA, including _N_6-methyladenosine (m6A), are deposited cotranscriptionally by writer proteins. WTAP guides METTL3/METTL14 to m6A-binding motifs. The m6A sites are recognized by nuclear or cytoplasmic reader proteins, which alter mRNA localization, degradation, or translation.

Figure 2.

Figure 2.. Role of METTL3 at heterochromatin.

The N _6_-methyladenosine (m 6 A) methyltransferase complex (MTC) that includes METTL3 methylates intracisternal A particle (IAP) mRNA and heterochromatic RNA (hetRNA). Binding of m6A by Ythdc1 is essential for the downstream deposition of H3K9me3 by Setdb1/Trim28. Methylated hetRNA associates with chromatin and facilitates the retention of HP1 and Suv39h proteins. H3K9me3, HP1, hetRNA, and Suv39h are lost upon Mettl3 depletion.

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