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N6-Methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2

Nature Genetics volume 52, pages 870–877 (2020)Cite this article

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Abstract

A dynamic epigenome is critical for appropriate gene expression in development and health1,2,3,4,5. Central to this is the intricate process of transcription6,7,8,9,10,11, which integrates cellular signaling with chromatin changes, transcriptional machinery and modifications to messenger RNA, such as N6-methyladenosine (m6A), 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 m6A-modified transcripts. We demonstrate that the methyltransferase METTL3/METTL14 regulates H3K9me2 modification. We observe a genome-wide correlation between m6A and occupancy by the H3K9me2 demethylase KDM3B, and we find that the m6A reader YTHDC1 physically interacts with and recruits KDM3B to m6A-associated chromatin regions, promoting H3K9me2 demethylation and gene expression. This study establishes a direct link between m6A and dynamic chromatin modification and provides mechanistic insight into the co-transcriptional interplay between RNA modifications and histone modifications.

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Fig. 1: Identification of histone modifications responding to m6A methylation.
Fig. 2: m6A methylation regulates H3K9me2 levels.
Fig. 3: Genome-wide correlation between m6A and KDM3B.
Fig. 4: RNA m6A co-transcriptionally directs KDM3B to target chromatin to demethylate H3K9me2.
Fig. 5: YTHDC1 recruits KDM3B to regulate H3K9me2.
Fig. 6: RNA m6A promotes H3K9me2-regulated gene expression.

Data availability

Protein expression data were downloaded from HPM database31. The histone ChIP–seq data for H3K9me2, H3K27me3, H3K4me, H3K4me3, H3K9me, H3K9me3, H3K27ac and H3K36me3 were downloaded from the NCBI GEO database with the accession numbers GSM1314605, GSM2596866, GSM1847705, GSM2938885, GSM1003751, GSM2386847, GSM1163096 and GSM2123549, respectively, for window correlation analysis (Extended Data Fig. 1). KDM6A ChIP–seq data from GSM1207791 were downloaded for signal visualization in (Extended Data Fig. 3). RNA-seq, m6A-seq and ChIP–seq raw data have been deposited in the Gene Expression Omnibus under accession code GSE153651 and the Genome Sequence Archive in BIG Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences under accession number CRA002304. Source data are provided with this paper.

Code availability

Custom code written in Python is available on Github (https://github.com/linjian-smu/m6AMethylation-K9me2).

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Acknowledgements

We thank K. Yen for discussion and critical reading of the manuscript. This work was supported by the National Key R&D Program of China (grant nos. 2018YFC1004103 and 2019YFA0802300), the Natural Science Foundation of China (grant nos. 31722034, 81771643, 31801234 and 31970595) and Pearl River S&T Nova Program of Guangzhou (grant no. 201806010009).

Author information

Author notes

  1. These authors contributed equally: Yuan Li, Linjian Xia, Kaifen Tan, Xidong Ye, Zhixiang Zuo, Minchun Li.

Authors and Affiliations

  1. Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, P. R. China

    Yuan Li, Linjian Xia, Kaifen Tan, Xidong Ye, Minchun Li, Zihan Wang, Xiaona Liu, Mingqiang Deng, Jinru Cui, Mengtian Yang, Sun Liu, Xin Cao, Haoran Zhu, Tianqi Liu, Jiaxin Hu, Junfang Shi, Shan Xiao & Laixin Xia

  2. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China

    Zhixiang Zuo

  3. Frontier Science Center for Immunology and Metabolism, Medical Research Institute, and Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, P. R. China

    Rui Xiao

  4. Department of Forensic Toxicology, School of Forensic Medicine, Southern Medical University, Guangzhou, P. R. China

    Qizhi Luo

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Contributions

Laixin Xia conceived the research. Laixin Xia and S.X. designed and supervised the project. Y.L., K.T., X.Y., R.X., J.S., X.L., M.D., M.L., M.Y., Z.W., S.L., H.Z., T.L., J.H. and Q.L. performed experiments. Linjian Xia, Z.Z., X.C. and J.C. conducted bioinformatic analysis. Laixin Xia and S.X. wrote the manuscript with input from all authors.

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Correspondence to Shan Xiao or Laixin Xia.

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Extended data

Extended Data Fig. 1 Screen for the epigenetic signals responding to RNA m6A methylation.

a, Schematic of PCR primers to identify the site-specifically integrated pcDNA5/FRT/To plasmid in Flp-in T-Rex 293 cell line. b, PCR products of reporters using SV40-F/FRT-R or BGH-F/FRT-R to verify integration status. c, Expression level of endogenous CEBPA and reporters normalized to ACTB. Error bars indicate mean ± SD of three independent experiments. d, The efficiency of METTL3 knockdown in reporters. The expression level of METTL3 was first normalized to ACTB then to siNC. Error bars indicate mean ± SD of three independent experiments. e, Consensus motif of m6A peaks on nascent RNA. Binomial distribution test. f, Pearson correlation coefficient analysis of m6A signals with H3K9me2 and H3K27me3, H3K9me, H3K9me2, H3K4me, H3K4me3, H3K27ac and H3K36me3 in nonoverlapping, nonrepetitive windows of different sizes (in kilobases) along the mouse genome. g, Heatmap showing the distribution of methylation level of m6A, H3K9me2 and H3K27me3 at m6A peaks on nascent RNA. h, Stacking bar chart showing the fraction of RNA modified by m6A in H3K9me2 or no H3K9me2 RNA groups. RNAs with similar exon number, expression level, transcript size or density of m6A motifs were randomly sampled and compared. P = 5.71e-121, 2.94e-07, 5.06e-69, 7.41e-28, 3.53e-55 from left to right, two-sided Fisher’s exact test.

Source data

Extended Data Fig. 2 RNA m6A regulates H3K9me2 methylation.

a, The mutation scheme of the METTL3-/- cell line. b, The mutation scheme of the METTL14-/- cell line. c, The mutation scheme of the FTO-/- cell line. d, Expression level of H3K9me2 and m6A methyltransferases and demethylases normalized to Actb. Error bars indicate mean ± SD of three independent experiments. e–h, Western blots of H3K9me2 in METTL3, METTL14, FTO or ALKBH5 knockdown HEK293T cells. H3 was used as a sample processing control. Two unique shRNAs were used. i. LC/MS-MS of m6A/A in WT and METTL3D395A. Error bars indicate mean ± SD of three independent experiments. j, Distribution of hypermethylated H3K9me2 regions on chromatin. k, LC/MS-MS of m6A/A in FTO and ALKBH5 knockdown HEK293 cells using shRNAs. shGFP served as a control. Bar represents average of two independent experiments. l, Clustered heatmap showing the hypermethylated and hypomethylated H3K9me2 regions in shFTO (left) or shALKBH5 (right) compared with shGFP cells. m, Distribution of hypomethylated H3K9me2 regions on chromatin in shFTO (upper) or shALKBH5 (lower) cells. n, Overlap between genes with decreased H3K9me2 signals and genes with increased m6A signals in shFTO cells (left) or shALKBH5 (right) versus shGFP. P= 5.22e-09 in ALKBH5 knockdown, P = 4.41e-21 in FTO knockdown, Hypergeometric distribution test.

Source data

Extended Data Fig. 3 Genome-wide correlation between m6A and KDM3B in H3K9me2 regulation.

a, Pearson correlation of METTL3 with KDM3B protein expression level in HPM database. ACTB served as a negative control. The gray shades represent the 95% confidence intervals of the linear regression model. b, Western blot showing the expression level of SFB-METTL3 and FLAG-KDM3B and endogenous METTL3 and KDM3B. c, Overlap between KDM3B-occupied genes and genes corresponding to m6A-modified transcripts after normalization with similar exon number, expression level, transcript length, m6A motif density, or splicing sites. P=0, 0, 0, 8.23e-107, 0 from left to right, hypergeometric distribution test. d, Heatmap showing RPKM of KDM3B and KDM6A ChIP–seq relative to m6A peak center. e, Heatmap showing RPKM of KDM3B and KDM6A ChIP–seq relative to METTL3 ChIP peak center. f, Distribution of KDM3B ChIP–seq tags relative to the m6A peak center. g, Distribution of KDM6A ChIP–seq tags relative to the METTL3 peak center.

Source data

Extended Data Fig. 4 m6A-dependent localization of KDM3B to target chromatin.

a, Western blot of the endogenous KDM3B in WT and METTL3D395A cells. TUBULIN serve as a loading control. b, Distribution of KDM3B ChIP–seq signals change around the center of METTL3 ChIP peaks in WT versus METTL3D395A cells. c, d, Heatmap showing RPKM of KDM3B ChIP–seq relative to m6A peak center (c) or METTL3 ChIP peak center (d) in WT and METTL3D395A. e, KDM3B ChIP–qPCR in WT and METTL3D395A cells. Error bars indicate mean ± SD of three independent experiments. f, Near-Infrared (NIR) western blot and quantification of H3K9me2 modification levels in WT and METTL3D395A cells before and after induced expression of Flag-KDM3B. Error bars indicate mean ± SD of five independent experiments in right panel. ** P = 0.0072, two-sided Student’s t test. g, NIR western blots and quantification of H3K9me2 in WT and METTL3D395A cells before and after vitamin C treatment. In F and G, H3 was used as a loading control. Error bars indicate mean ± SD of five independent experiments in right panel, ** P = 0.005, two-sided Student’s t test.

Source data

Extended Data Fig. 5 YTHDC1 recruits KDM3B to regulate H3K9me2.

a, Co-IP of SFB-KDM3B with MYC tagged m6A readers YTHDC1, YTHDF2 and HNRNPA2B1 in HEK293T cells. b, Fluorescence immunostaining of endogenous KDM3B and YTHDC1 in mES or HEK293T. Scale bar: 2 μM. c, Western blot of the H3K9me2 modification level after YTHDC1 knockdown by two siRNAs in HEK293T. The decrease of YTHDC1 were also shown. H3 served as sample processing control. d, ChIP–qPCR of KDM3B in shGFP and shYTHDC1 mES cells. Enrichment of ChIP versus input chromatin was normalized against spike-in drosophila chromatin. Error bars indicate mean ± SD of three independent experiments.

Source data

Extended Data Fig. 6 The relationship between gene expression, m6A peak density and H3K9me2 abundance.

a, Heatmap showing the relationship between gene expression, m6A peak density and H3K9me2 abundance in m6A modified transcripts with increased H3K9me2 signals after METTL3 mutation, other m6A modified transcripts without H3K9me2 increase, and non-m6A modified transcripts in METTL3D395A versus WT cells.

Supplementary information

Reporting Summary

Supplementary Table 1

List of primers used in this study.

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Li, Y., Xia, L., Tan, K. et al. N6-Methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2. Nat Genet 52, 870–877 (2020). https://doi.org/10.1038/s41588-020-0677-3

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