TY - JOUR
T1 - Depletion of H3K36me2 recapitulates epigenomic and phenotypic changes induced by the H3.3K36M oncohistone mutation
AU - Rajagopalan, Kartik N.
AU - Chen, Xiao
AU - Weinberg, Daniel N.
AU - Chen, Haifen
AU - Majewski, Jacek
AU - Allis, C. David
AU - Lu, Chao
N1 - Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/3/2
Y1 - 2021/3/2
N2 - Hotspot histone H3 mutations have emerged as drivers of oncogenesis in cancers of multiple lineages. Specifically, H3 lysine 36 to methionine (H3K36M) mutations are recurrently identified in chondroblastomas, undifferentiated sarcomas, and head and neck cancers. While the mutation reduces global levels of both H3K36 dimethylation (H3K36me2) and trimethylation (H3K36me3) by dominantly inhibiting their respective specific methyltransferases, the relative contribution of these methylation states to the chromatin and phenotypic changes associated with H3K36M remains unclear. Here, we specifically deplete H3K36me2 or H3K36me3 in mesenchymal cells, using CRISPR-Cas9 to separately knock out the corresponding methyltransferases NSD1/2 or SETD2. By profiling and comparing the epigenomic and transcriptomic landscapes of these cells with cells expressing the H3.3K36M oncohistone, we find that the loss of H3K36me2 could largely recapitulate H3.3K36M's effect on redistribution of H3K27 trimethylation (H3K27me3) and gene expression. Consistently, knockout of Nsd1/ 2, but not Setd2, phenocopies the differentiation blockade and hypersensitivity to the DNA-hypomethylating agent induced by H3K36M. Together, our results support a functional divergence between H3K36me2 and H3K36me3 and their nonredundant roles in H3K36M-driven oncogenesis.
AB - Hotspot histone H3 mutations have emerged as drivers of oncogenesis in cancers of multiple lineages. Specifically, H3 lysine 36 to methionine (H3K36M) mutations are recurrently identified in chondroblastomas, undifferentiated sarcomas, and head and neck cancers. While the mutation reduces global levels of both H3K36 dimethylation (H3K36me2) and trimethylation (H3K36me3) by dominantly inhibiting their respective specific methyltransferases, the relative contribution of these methylation states to the chromatin and phenotypic changes associated with H3K36M remains unclear. Here, we specifically deplete H3K36me2 or H3K36me3 in mesenchymal cells, using CRISPR-Cas9 to separately knock out the corresponding methyltransferases NSD1/2 or SETD2. By profiling and comparing the epigenomic and transcriptomic landscapes of these cells with cells expressing the H3.3K36M oncohistone, we find that the loss of H3K36me2 could largely recapitulate H3.3K36M's effect on redistribution of H3K27 trimethylation (H3K27me3) and gene expression. Consistently, knockout of Nsd1/ 2, but not Setd2, phenocopies the differentiation blockade and hypersensitivity to the DNA-hypomethylating agent induced by H3K36M. Together, our results support a functional divergence between H3K36me2 and H3K36me3 and their nonredundant roles in H3K36M-driven oncogenesis.
KW - Cancer
KW - Chromatin and epigenomics
KW - H3K36 methylation
KW - NSD
KW - Oncohistone
UR - http://www.scopus.com/inward/record.url?scp=85101647120&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85101647120&partnerID=8YFLogxK
U2 - 10.1073/pnas.2021795118
DO - 10.1073/pnas.2021795118
M3 - Article
C2 - 33619101
AN - SCOPUS:85101647120
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 9
M1 - e2021795118
ER -