Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones.

Autor:	Sarthy JF; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States.; Cancer and Blood Disorders, Seattle, United States., Meers MP; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Janssens DH; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Henikoff JG; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Feldman H; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Paddison PJ; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Lockwood CM; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, United States., Vitanza NA; Cancer and Blood Disorders, Seattle, United States.; Clinical Research Division Fred Hutchinson Cancer Research Center, Seattle, United States., Olson JM; Cancer and Blood Disorders, Seattle, United States.; Clinical Research Division Fred Hutchinson Cancer Research Center, Seattle, United States., Ahmad K; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States., Henikoff S; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States.; Howard Hughes Medical Institute, Chevy Chase, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2020 Sep 09; Vol. 9. Date of Electronic Publication: 2020 Sep 09.
DOI:	10.7554/eLife.61090
Abstrakt:	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. Competing Interests: JS, MM, DJ, JH, HF, PP, CL, NV, JO, KA, SH No competing interests declared (© 2020, Sarthy et al.)
Databáze:	MEDLINE
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