组蛋白H3
核小体
生物
组蛋白密码
表观遗传学
组蛋白甲基化
染色质重塑
组蛋白甲基转移酶
组蛋白H2A
H3K4me3
表观遗传学
异染色质
作者
Jay F. Sarthy,Michael P. Meers,Derek H. Janssens,Steven Henikoff,Heather Feldman,Patrick J. Paddison,Christina M. Lockwood,Nicholas A. Vitanza,James M. Olson,Kami Ahmad,Steven Henikoff
出处
期刊:eLife
[eLife Sciences Publications, Ltd.]
日期:2020-09-09
卷期号:9
被引量:41
摘要
Lysine 27-to-methionine (K27M) mutations in the H3.1 or H3.3 histone genes are characteristic of pediatric diffuse midline gliomas (DMGs). These oncohistone mutations dominantly inhibit histone H3K27 trimethylation and silencing, but it is unknown how oncohistone type affects gliomagenesis. We show that the genomic distributions of H3.1 and H3.3 oncohistones in human patient-derived DMG cells are consistent with the DNAreplication-coupled deposition of histone H3.1 and the predominant replication-independent deposition of histone H3.3. Although H3K27 trimethylation is reduced for both oncohistone types, H3.3K27M-bearing cells retain some domains, and only H3.1K27M-bearing cells lack H3K27 trimethylation. Neither oncohistone interferes with PRC2 binding. Using Drosophila as a model, we demonstrate that inhibition of H3K27 trimethylation occurs only when H3K27M oncohistones are deposited into chromatin and only when expressed in cycling cells. We propose that oncohistones inhibit the H3K27 methyltransferase as chromatin patterns are being duplicated in proliferating cells, predisposing them to tumorigenesis.
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