TY - JOUR
T1 - H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis
AU - Harutyunyan, Ashot S.
AU - Krug, Brian
AU - Chen, Haifen
AU - Papillon-Cavanagh, Simon
AU - Zeinieh, Michele
AU - De Jay, Nicolas
AU - Deshmukh, Shriya
AU - Chen, Carol C.L.
AU - Belle, Jad
AU - Mikael, Leonie G.
AU - Marchione, Dylan M.
AU - Li, Rui
AU - Nikbakht, Hamid
AU - Hu, Bo
AU - Cagnone, Gael
AU - Cheung, Warren A.
AU - Mohammadnia, Abdulshakour
AU - Bechet, Denise
AU - Faury, Damien
AU - McConechy, Melissa K.
AU - Pathania, Manav
AU - Jain, Siddhant U.
AU - Ellezam, Benjamin
AU - Weil, Alexander G.
AU - Montpetit, Alexandre
AU - Salomoni, Paolo
AU - Pastinen, Tomi
AU - Lu, Chao
AU - Lewis, Peter W.
AU - Garcia, Benjamin A.
AU - Kleinman, Claudia L.
AU - Jabado, Nada
AU - Majewski, Jacek
N1 - Funding Information:
This work was supported by funding from: US National Institutes of Health (NIH grant P01-CA196539 to N.J., J.M., P.W.L., B.A.G., T.P.; GM110174 to B.A.G.; T32GM008275 and TL1TR001880 to D.M.M.), the Canadian Institutes for Health Research (CIHR grant MOP-286756 and FDN-154307 to N.J., EP1–120608 to T.P. and P.J.T.-156086 to C.L.K.), the Fonds de Recherche du Québec en Santé (FRQS) salary award to C.L.K. N.J. is a member of the Penny Cole Laboratory and the recipient of a Chercheur Boursier, Chaire de Recherche Award from the FRQS. This work was performed within the context of the International CHildhood Astrocytoma INtegrated Genomic and Epigenomic (ICHANGE) consortium, and the Stand Up to Cancer, Canada Cancer Stem Cell Dream Team initiative, with funding from Genome Canada and Genome Quebec. A.S.H., W.A.C., and N.D.J. are recipients of fellowships from FRQS. D.B. is the recipient of a fellowship from the TD CanadaTrust/ Montreal Children’s Hospital Foundation. M.K.M. is funded by a CIHR Banting postdoctoral fellowship. P.W.L. is a Pew Scholar in the Biomedical Sciences. C.L. acknowledges support from Damon Runyon Cancer Research Foundation and Matthew Larson Foundation. P.S. and M.P. are supported by the ERC (H3.3Cancer). We thank Alexey Soshnev for providing the comprehensive schema for the K27M mechanism of action. We are especially grateful for the generous philanthropic donations of Kat D DIPG and We Love You Connie Foundations.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.3K27M cells. H3K27me3 is unable to spread from large unmethylated CpG islands, while H3K27me2 can be deposited outside these PRC2 high-affinity sites but to levels corresponding to H3K27me3 deposition in wild-type cells. Our findings indicate that PRC2 recruitment and propagation on chromatin are seemingly unaffected by K27M, which mostly impairs spread of the repressive marks it catalyzes, especially H3K27me3. Genome-wide loss of H3K27me3 and me2 deposition has limited transcriptomic consequences, preferentially affecting lowly-expressed genes regulating neurogenesis. Removal of H3K27M restores H3K27me2/me3 spread, impairs cell proliferation, and completely abolishes their capacity to form tumors in mice.
AB - Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.3K27M cells. H3K27me3 is unable to spread from large unmethylated CpG islands, while H3K27me2 can be deposited outside these PRC2 high-affinity sites but to levels corresponding to H3K27me3 deposition in wild-type cells. Our findings indicate that PRC2 recruitment and propagation on chromatin are seemingly unaffected by K27M, which mostly impairs spread of the repressive marks it catalyzes, especially H3K27me3. Genome-wide loss of H3K27me3 and me2 deposition has limited transcriptomic consequences, preferentially affecting lowly-expressed genes regulating neurogenesis. Removal of H3K27M restores H3K27me2/me3 spread, impairs cell proliferation, and completely abolishes their capacity to form tumors in mice.
UR - http://www.scopus.com/inward/record.url?scp=85063281522&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-09140-x
DO - 10.1038/s41467-019-09140-x
M3 - Article
C2 - 30890717
AN - SCOPUS:85063281522
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1262
ER -