Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones
- Fred Hutchinson Cancer Research Center, United States
- University of Washington, United States
- Seattle Childrens Hospital, United States
Abstract
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 DNA replication-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.
Data availability
Sequencing data have been deposited in GEO under accession code GSE118099
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Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistonesNCBI Gene Expression Omnibus, GSE118099.
Article and author information
Author details
Funding
Howard Hughes Medical Institute (Henikoff)
- Steven Henikoff
National Institutes of Health (R01GM108699)
- Kami Ahmad
Alex's Lemonade Stand Foundation for Childhood Cancer (Sarthy)
- Jay F Sarthy
Damon Runyon Cancer Research Foundation (Sarthy)
- Jay F Sarthy
National Institutes of Health (T32 CA009351)
- Jay F Sarthy
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jerry L Workman, Stowers Institute for Medical Research, United States
Version history
- Received: July 15, 2020
- Accepted: September 8, 2020
- Accepted Manuscript published: September 9, 2020 (version 1)
- Version of Record published: September 25, 2020 (version 2)
Copyright
© 2020, Sarthy et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones
eLife 9:e61090.
https://doi.org/10.7554/eLife.61090
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