Histone H3 trimethylation at lysine 36 guides m6A RNA modification co-transcriptionally
Histone H3 trimethylation at lysine 36 guides m6A RNA modification co-transcriptionally
复制标题
赖氨酸 36 处的组蛋白 H3 三甲基化引导 m(6)A RNA 共转录修饰
DOI：
10.1038/s41586-019-1016-7
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发表时间：
2019-03-21
期刊：
影响因子：
64.8
通讯作者：
Chen, Jianjun
中科院分区：
文献类型：
--
作者：
Huang, Huilin;Weng, Hengyou;Chen, Jianjun
DNA和组蛋白修饰对基因表达有显著影响（1）。作为mRNA中最普遍的内部修饰，N-6-甲基腺苷（m（6）A）mRNA修饰作为基因调控的重要转录后机制（2-4）并且在各种正常和病理过程中具有关键作用（5-12）。然而，目前还不清楚m（6）A是如何特异性地和动态地沉积在转录组中的。在这里，我们报告组蛋白H3三甲基化在Lys 36（H3 K36 me 3），转录延伸的标记，引导m（6）A沉积全球。我们发现，m（6）A修饰在H3 K36 me 3峰附近富集，当细胞H3 K36 me 3耗尽时，m（6）A修饰整体减少。在机制上，H3 K36 me 3被m（6）A甲基转移酶复合物（MTC）的关键组分--胃L14直接识别和结合，胃L14又促进m（6）A MTC与相邻RNA聚合酶II的结合，从而将m（6）A MTC递送至活跃转录的新生RNA以共转录方式存款m（6）A。在小鼠胚胎干细胞中，表型复制的胃L14敲除，H3 K36 me 3消耗也显著降低m（6）A丰度转录组和多能性转录物，导致细胞干细胞性增加。总的来说，我们的研究揭示了H3 K36 me 3和胃L14在决定m（6）A在mRNA中的特异性和动态沉积中的重要作用，并揭示了另一层基因表达调控，涉及组蛋白修饰和RNA甲基化之间的串扰。
DNA and histone modifications have notable effects on gene expression(1). Being the most prevalent internal modification in mRNA, the N-6-methyladenosine (m(6)A) mRNA modification is as an important post-transcriptional mechanism of gene regulation(2-4) and has crucial roles in various normal and pathological processes(5-12). However, it is unclear how m(6)A is specifically and dynamically deposited in the transcriptome. Here we report that histone H3 trimethylation at Lys36 (H3K36me3), a marker for transcription elongation, guides m(6)A deposition globally. We show that m(6)A modifications are enriched 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 crucial 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, 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 knockdown, H3K36me3 depletion also markedly reduces m(6)A abundance transcriptome-wide and in pluripotency transcripts, resulting in increased cell stemness. Collectively, our studies reveal the important roles of H3K36me3 and METTL14 in determining specific and dynamic deposition of m(6)A in mRNA, and uncover another layer of gene expression regulation that involves crosstalk between histone modification and RNA methylation.