N-Methyladenosine Co-transcriptionally Directs the Demethylation of Histone H3K9me2

Overview

Journal Nat Genet

Specialty Genetics

Date 2020 Aug 12

PMID 32778823

Citations 129

Authors

Yuan Li

Linjian Xia

Kaifen Tan

Xidong Ye

Zhixiang Zuo

Minchun Li

Rui Xiao

Zihan Wang

Xiaona Liu

Mingqiang Deng

Jinru Cui

Mengtian Yang

Qizhi Luo

Sun Liu

Xin Cao

Haoran Zhu

Tianqi Liu

Jiaxin Hu

Junfang Shi

Shan Xiao

Laixin Xia

Affiliations

Soon will be listed here.

Abstract

A dynamic epigenome is critical for appropriate gene expression in development and health. Central to this is the intricate process of transcription, which integrates cellular signaling with chromatin changes, transcriptional machinery and modifications to messenger RNA, such as N-methyladenosine (mA), which is co-transcriptionally incorporated. The integration of these aspects of the dynamic epigenome, however, is not well understood mechanistically. Here we show that the repressive histone mark H3K9me2 is specifically removed by the induction of mA-modified transcripts. We demonstrate that the methyltransferase METTL3/METTL14 regulates H3K9me2 modification. We observe a genome-wide correlation between mA and occupancy by the H3K9me2 demethylase KDM3B, and we find that the mA reader YTHDC1 physically interacts with and recruits KDM3B to mA-associated chromatin regions, promoting H3K9me2 demethylation and gene expression. This study establishes a direct link between mA and dynamic chromatin modification and provides mechanistic insight into the co-transcriptional interplay between RNA modifications and histone modifications.

Citing Articles

YTHDC1 negatively regulates UBE3A to influence RAD51 ubiquitination and inhibit apoptosis in colorectal cancer cells.

Gao M, Wu Y, Zhang L, Zhou Y, Liu H, Zhang W Sci Rep. 2025; 15(1):8857.

PMID: 40087295 DOI: 10.1038/s41598-025-92925-6.

The Role of MA Modification in Autoimmunity: Emerging Mechanisms and Therapeutic Implications.

Xu L, Shen T, Li Y, Wu X Clin Rev Allergy Immunol. 2025; 68(1):29.

PMID: 40085180 DOI: 10.1007/s12016-025-09041-6.

mRNA mA regulates gene expression via H3K4me3 shift in 5' UTR.

Yang Y, Huang Y, Wang T, Li S, Jiang J, Chen S Genome Biol. 2025; 26(1):54.

PMID: 40075435 PMC: 11900566. DOI: 10.1186/s13059-025-03515-8.

Mettl3/Eed/Ythdc1 regulatory axis controls endometrial receptivity and function.

Hu X, Li J, Ding C, Jiang J, Xia W, Lu J Commun Biol. 2025; 8(1):215.

PMID: 39934221 PMC: 11814224. DOI: 10.1038/s42003-025-07667-y.

Colonic stem cell from severe ulcerative colitis maintains environment-independent immune activation by altering chromatin accessibility and global mA loss.

Liu C, Li J, Jin H, Zhao Q, Li F, Huang Z Life Med. 2025; 2(4):lnad034.

PMID: 39872548 PMC: 11749566. DOI: 10.1093/lifemedi/lnad034.

References

Bonasio R, Tu S, Reinberg D . Molecular signals of epigenetic states. Science. 2010; 330(6004):612-6. PMC: 3772643. DOI: 10.1126/science.1191078. View

Elgin S, Reuter G . Position-effect variegation, heterochromatin formation, and gene silencing in Drosophila. Cold Spring Harb Perspect Biol. 2013; 5(8):a017780. PMC: 3721279. DOI: 10.1101/cshperspect.a017780. View

Allis C, Jenuwein T . The molecular hallmarks of epigenetic control. Nat Rev Genet. 2016; 17(8):487-500. DOI: 10.1038/nrg.2016.59. View

Shi Y, Lan F, Matson C, Mulligan P, Whetstine J, Cole P . Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004; 119(7):941-53. DOI: 10.1016/j.cell.2004.12.012. View

Tsukada Y, Fang J, Erdjument-Bromage H, Warren M, Borchers C, Tempst P . Histone demethylation by a family of JmjC domain-containing proteins. Nature. 2005; 439(7078):811-6. DOI: 10.1038/nature04433. View

Rea S, Eisenhaber F, OCarroll D, Strahl B, Sun Z, Schmid M . Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature. 2000; 406(6796):593-9. DOI: 10.1038/35020506. View

Klose R, Kallin E, Zhang Y . JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet. 2006; 7(9):715-27. DOI: 10.1038/nrg1945. View

Nicetto D, Zaret K . Role of H3K9me3 heterochromatin in cell identity establishment and maintenance. Curr Opin Genet Dev. 2019; 55:1-10. PMC: 6759373. DOI: 10.1016/j.gde.2019.04.013. View

Volpe T, Kidner C, Hall I, Teng G, Grewal S, Martienssen R . Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science. 2002; 297(5588):1833-7. DOI: 10.1126/science.1074973. View

10.

Reinhart B, Bartel D . Small RNAs correspond to centromere heterochromatic repeats. Science. 2002; 297(5588):1831. DOI: 10.1126/science.1077183. View

11.

Verdel A, Jia S, Gerber S, Sugiyama T, Gygi S, Grewal S . RNAi-mediated targeting of heterochromatin by the RITS complex. Science. 2004; 303(5658):672-6. PMC: 3244756. DOI: 10.1126/science.1093686. View

12.

Li S, Mason C . The pivotal regulatory landscape of RNA modifications. Annu Rev Genomics Hum Genet. 2014; 15:127-50. DOI: 10.1146/annurev-genom-090413-025405. View

13.

Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S . Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012; 485(7397):201-6. DOI: 10.1038/nature11112. View

14.

Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y . N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011; 7(12):885-7. PMC: 3218240. DOI: 10.1038/nchembio.687. View

15.

Meyer K, Saletore Y, Zumbo P, Elemento O, Mason C, Jaffrey S . Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons. Cell. 2012; 149(7):1635-46. PMC: 3383396. DOI: 10.1016/j.cell.2012.05.003. View

16.

Frye M, Harada B, Behm M, He C . RNA modifications modulate gene expression during development. Science. 2018; 361(6409):1346-1349. PMC: 6436390. DOI: 10.1126/science.aau1646. View

17.

Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L . A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2013; 10(2):93-5. PMC: 3911877. DOI: 10.1038/nchembio.1432. View

18.

Huang H, Weng H, Zhou K, Wu T, Zhao B, Sun M . Histone H3 trimethylation at lysine 36 guides mA RNA modification co-transcriptionally. Nature. 2019; 567(7748):414-419. PMC: 6438714. DOI: 10.1038/s41586-019-1016-7. View

19.

Liu J, Dou X, Chen C, Chen C, Liu C, Xu M . -methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription. Science. 2020; 367(6477):580-586. PMC: 7213019. DOI: 10.1126/science.aay6018. View

20.

Yang Y, Hsu P, Chen Y, Yang Y . Dynamic transcriptomic mA decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res. 2018; 28(6):616-624. PMC: 5993786. DOI: 10.1038/s41422-018-0040-8. View