Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression.
Chromatin
/ genetics
Gene Expression
/ genetics
Gene Expression Regulation
/ genetics
Glioma
/ pathology
HEK293 Cells
Histone-Lysine N-Methyltransferase
/ metabolism
Histones
/ genetics
Humans
Lysine
/ metabolism
Mesenchymal Stem Cells
/ metabolism
Methylation
Mutation
/ genetics
Neoplastic Processes
Polycomb Repressive Complex 1
/ genetics
Polycomb Repressive Complex 2
/ genetics
Protein Processing, Post-Translational
H3.3 G34 mutations
NSD1/2
PRC2
SETD2
oncohistones
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
03 11 2020
03 11 2020
Historique:
pubmed:
18
10
2020
medline:
5
1
2021
entrez:
17
10
2020
Statut:
ppublish
Résumé
A high percentage of pediatric gliomas and bone tumors reportedly harbor missense mutations at glycine 34 in genes encoding histone variant H3.3. We find that these H3.3 G34 mutations directly alter the enhancer chromatin landscape of mesenchymal stem cells by impeding methylation at lysine 36 on histone H3 (H3K36) by SETD2, but not by the NSD1/2 enzymes. The reduction of H3K36 methylation by G34 mutations promotes an aberrant gain of PRC2-mediated H3K27me2/3 and loss of H3K27ac at active enhancers containing SETD2 activity. This altered histone modification profile promotes a unique gene expression profile that supports enhanced tumor development in vivo. Our findings are mirrored in G34W-containing giant cell tumors of bone where patient-derived stromal cells exhibit gene expression profiles associated with early osteoblastic differentiation. Overall, we demonstrate that H3.3 G34 oncohistones selectively promote PRC2 activity by interfering with SETD2-mediated H3K36 methylation. We propose that PRC2-mediated silencing of enhancers involved in cell differentiation represents a potential mechanism by which H3.3 G34 mutations drive these tumors.
Identifiants
pubmed: 33067396
pii: 2006076117
doi: 10.1073/pnas.2006076117
pmc: PMC7959516
doi:
Substances chimiques
Chromatin
0
Histones
0
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Polycomb Repressive Complex 2
EC 2.1.1.43
SETD2 protein, human
EC 2.1.1.43
Polycomb Repressive Complex 1
EC 2.3.2.27
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
27354-27364Subventions
Organisme : NCI NIH HHS
ID : R00 CA212257
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA224971
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014520
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA196539
Pays : United States
Organisme : CIHR
Pays : Canada
Organisme : NIH HHS
ID : DP2 OD007447
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007739
Pays : United States
Organisme : NCATS NIH HHS
ID : TL1 TR001880
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008275
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI118891
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM110174
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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