Histone H3 trimethylation at lysine 36 guides m6A RNA modification co-transcriptionally

Abstract

DNA and histone modifications exhibit noticeable impacts on gene expression 1 . Being the most prevalent internal modification in mRNA, N 6 -Methyladenosine (m 6 A) mRNA modification emerges as an important post-transcriptional mechanism of gene regulation 2 - 4 and plays critical roles in various normal and pathological bioprocesses 5 - 12 . However, how m 6 A is precisely and dynamically deposited in the transcriptome remains elusive. Here we report that H3K36me3 histone modification, a marker for transcription elongation, globally guides m 6 A modification. We found that m 6 A modifications enrich in the vicinity of H3K36me3 peaks, and are reduced globally when cellular H3K36me3 is depleted. Mechanistically, H3K36me3 is recognized and bound directly by METTL14, a critical component of the m 6 A methyltransferase complex (MTC), which in turn facilitates the binding of the m 6 A MTC to adjacent RNA polymerase II, and thereby delivering the m 6 A MTC to actively transcribed nascent RNAs to deposit m 6 A co-transcriptionally. In mouse embryonic stem cells, phenocopying Mettl14 silencing, H3K36me3 depletion also induces m 6 A reduction transcriptome-wide and in pluripotency transcripts, resulting in increased cell stemness. Collectively, our studies reveal the critical roles of H3K36me3 and METTL14 in determining precise and dynamic m 6 A deposition in mRNA, and uncover another layer of gene expression regulation involving crosstalk between histone modification and RNA methylation.

REPIC: A database for exploringN6-methyladenosine methylome

“…5c, we observe H3K4me3 and DNase-seq peaks are located in the promoter region of the NANOG gene, indicating that it is actively transcribed in hESCs [12]. We also note that m 6 A modifications at the stop codon region are enriched with H3K36me3 peaks, which is consistent with the recently reported mechanism of m 6 A modification deposition [32].…”

“…Unfortunately, all the above databases except CVm6A simply combined m 6 A peaks across datasets without considering the cell type-or tissue-specificity. Furthermore, recent studies uncovered the associations of m 6 A modifications with promoters [29][30][31] and histone marks [32,33], offering new insights into potential regulation pathways and underlying mechanisms, through which m 6 A could influence transcriptional regulation and gene expression. However, to our knowledge, m 6 A modifications and epigenomic data have not been curated well together.…”

YTHDF2 promotes mitotic entry and is regulated by cell cycle mediators

“…Methyltransferase Like 3 (METTL3) and METTL14 [1]-together with several key components, such as Wilms tumor 1-associated protein (WTAP) [2], Vir Like m 6 A Methyltransferase Associated (VIRMA) [3], and Zinc Finger CCCH-Type Containing 13 (ZC3H13) [4]-form a methyltransferase complex to mediate N 6 -methyladenosine (m 6 A) modification on mRNAs in a co-transcriptional manner [5,6]. m 6 A, the most abundant modification on mRNAs, plays multifaceted roles in regulating pre-mRNA processing [7,8], nuclear export [9], stability [10], translation [11], and other biochemical properties [12,13] of mRNA in eukaryotes. The myriad roles of the m 6 A modification mostly rely on downstream RNA-binding proteins, known as m 6 A "readers," that preferentially recognize m 6 A-modified RNAs [9][10][11]14,15].…”

“…m 6 A, the most abundant modification on mRNAs, plays multifaceted roles in regulating pre-mRNA processing [7,8], nuclear export [9], stability [10], translation [11], and other biochemical properties [12,13] of mRNA in eukaryotes. The myriad roles of the m 6 A modification mostly rely on downstream RNA-binding proteins, known as m 6 A "readers," that preferentially recognize m 6 A-modified RNAs [9][10][11]14,15]. YTH N 6 -methyladenosine RNA binding protein 2 (YTHDF2) was the first functionally verified m 6 A reader to promote the degradation of m 6 A-modified mRNAs in humans [10].…”

Targeted mRNA demethylation using an engineered dCas13b-ALKBH5 fusion protein

“…Current methods of manipulating RNA methylation are primarily based on modulating the expression of RNA methyltransferases (Mettl3/Mettl14/WTAP complex) or demethylase (FTO and/or ALKBH5) via bioengineering methods, which cause broad epigenetic changes and activation of endogenous retroviruses 9,[11][12][13][14] . Recently, flavin mononucleotide was identified as a cell active artificial m 6 A RNA demethylase, which provided a potential and powerful small molecule for RNA demethylation 15 .…”