Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression

Siddhant U. Jain, Sima Khazaei, Dylan M. Marchione, Stefan M. Lundgren, Xiaoshi Wang, Daniel N. Weinberg, Shriya Deshmukh, Nikoleta Juretic, Chao Lu, C. David Allis, Benjamin A. Garcia, Nada Jabado, Peter W. Lewis

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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.

Original languageEnglish
Pages (from-to)27354-27364
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number44
StatePublished - Nov 3 2020


  • H3.3 G34 mutations
  • NSD1/2
  • Oncohistones
  • PRC2
  • SETD2


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