Driving Chromatin Organisation through N6-methyladenosine Modification of RNA: What Do We Know and What Lies Ahead?

Abstract

In recent years, there has been an increase in research efforts surrounding RNA modification thanks to key breakthroughs in NGS-based whole transcriptome mapping methods. More than 100 modifications have been reported in RNAs, and some have been mapped at single-nucleotide resolution in the mammalian transcriptome. This has opened new research avenues in fields such as neurobiology, developmental biology, and oncology, among others. To date, we know that the RNA modification machinery finely tunes many diverse mechanisms involved in RNA processing and translation to regulate gene expression. However, it appears obvious to the research community that we have only just begun the process of understanding the several functions of the dynamic web of RNA modification, or the "epitranscriptome". To expand the data generated so far, recently published studies revealed a dual role for N6-methyladenosine (m6A), the most abundant mRNA modification, in driving both chromatin dynamics and transcriptional output. These studies showed that the m6A-modified, chromatin-associated RNAs could act as molecular docks, recruiting histone modification proteins and thus contributing to the regulation of local chromatin structure. Here, we review these latest exciting findings and outline outstanding research questions whose answers will help to elucidate the biological relevance of the m6A modification of chromatin-associated RNAs in mammalian cells.

Keywords: LLPS (Liquid–Liquid Phase Separation); N6-methyladenosine; chromatin; chromatin-associated RNAs; histone modifications; transcription; transposable elements.

Figure 1

The regulation of transposable elements and chromatin accessibility by m6A. (A) METTL3-dependent methylation of carRNAs maintains condensed chromatin at intergenic regions and promotes carRNAs degradation by the NEXT (nuclear exosome targeting) complex. Loss of carRNA methylation leads to increased chromatin accessibility and enriched transcription, associated with increased histone H3-lysine4 trimethylation (H3K4me3) and histone H3-lysine27 acetylation (H3K27ac). carRNAs can now recruit epigenetic factors such as YY1 and EP300 to maintain an open chromatin conformation and downstream transcription. (B) METTL3 deposits m6A on intracisternal A particle (IAP) RNAs. YTHDC1 recognises and binds to methylated IAPs, and in conjunction with METTL3 recruits the histone methyltrasferase SETDB1 and its co-factor TRIM28. This complex establishes histone H3-lysine9 trimethylation and maintains a closed chromatin conformation at IAP loci. This leads to an overall reduction in the transcription of IAP RNAs. m6A-marked IAP RNAs are degraded by YTHDF2. (C) m6A-marked LINE1 silences the Dux1 locus in mouse embryonic stem cells to prevent the activation of the 2C-like state transcriptional program. Methylated LINE1 recruits the methyltransferse SETDB1 and its co-factor TRIM28 through YTHDC1. Nucleolin also takes part in the silencing complex assembled over the m6A-marked LINE1. Created with BioRender.com.

Figure 2

The interplay between histone modifications, gene transcription, and m6A. (A) METTL3-dependent methylation of mRNAs recruits YTHDC1, which in turn loads histone demethylase KDM3B to remove histone H3-lysine9 dimethylation (H3K9me2) and promote gene transcription. (B) Histone H3-lysine36 trimethylation (H3K36me3) recruits the m6A methyltransferase complex onto accessible chromatin, and promotes the methylation of newly transcribed mRNAs. Created with BioRender.com.