H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis

被引：225

作者：

Harutyunyan, Ashot S. ^{[1
]}

Krug, Brian ^{[1
]}

Chen, Haifen ^{[1
]}

Papillon-Cavanagh, Simon ^{[1
]}

Zeinieh, Michele ^{[1
]}

De Jay, Nicolas ^{[1
,2
]}

Deshmukh, Shriya ^{[1
]}

Chen, Carol C. L. ^{[1
]}

Belle, Jad ^{[1
]}

Mikael, Leonie G. ^{[3
,4
]}

Marchione, Dylan M. ^{[5
,6
]}

Li, Rui ^{[1
]}

Nikbakht, Hamid ^{[1
]}

Hu, Bo ^{[1
]}

Cagnone, Gael ^{[1
]}

Cheung, Warren A. ^{[1
,7
]}

Mohammadnia, Abdulshakour ^{[1
]}

Bechet, Denise ^{[1
]}

Faury, Damien ^{[1
]}

McConechy, Melissa K. ^{[1
]}

Pathania, Manav ^{[8
]}

Jain, Siddhant U. ^{[9
,10
]}

Ellezam, Benjamin ^{[11
]}

Weil, Alexander G. ^{[12
]}

Montpetit, Alexandre ^{[13
,14
]}

Salomoni, Paolo ^{[8
,15
]}

Pastinen, Tomi ^{[1
,7
]}

Lu, Chao ^{[16
]}

Lewis, Peter W. ^{[9
,10
]}

Garcia, Benjamin A. ^{[5
,6
]}

Kleinman, Claudia L. ^{[1
,2
]}

Jabado, Nada ^{[1
,3
,4
]}

Majewski, Jacek ^{[1
,13
,14
]}

机构：

[1] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada

[2] Jewish Gen Hosp, Lady Davis Res Inst, Montreal, PQ H3T 1E2, Canada

[3] McGill Univ, Dept Pediat, Montreal, PQ H4A 3J1, Canada

[4] McGill Univ Hlth Ctr, Res Inst, Montreal, PQ H4A 3J1, Canada

[5] Univ Penn, Perelman Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA

[6] Univ Penn, Perelman Sch Med, Penn Epigenet Inst, Philadelphia, PA 19104 USA

[7] Childrens Mercy Kansas City, Ctr Pediat Genom Med, Kansas City, MO 64108 USA

[8] UCL, Canc Inst, Samantha Dickson Brain Canc Unit, London WCE1 6DD, England

[9] Univ Wisconsin, Dept Biomol Chem, Sch Med & Publ Hlth, Madison, WI 53715 USA

[10] Univ Wisconsin, Wisconsin Inst Discovery, Madison, WI 53715 USA

[11] Univ Montreal, Ctr Hosp Univ St Justine, Dept Pathol, Montreal, PQ H3T 1C5, Canada

[12] Univ Montreal, Ctr Hosp Univ St Justine, Dept Pediat Neurosurg, Montreal, PQ H3T 1C5, Canada

[13] McGill Univ, Montreal, PQ H3A 0G1, Canada

[14] Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada

[15] German Ctr Neurodegenerat Dis, Nucl Funct CNS Pathophysiol, D-53127 Bonn, Germany

[16] Columbia Univ, Dept Genet & Dev, Irving Med Ctr, New York, NY 10032 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

美国国家卫生研究院;

关键词：

PEDIATRIC HIGH-GRADE; ADULT GLIOBLASTOMA; GENE-EXPRESSION; HISTONE H3.3; LYSINE; 27; DE-NOVO; POLYCOMB; MUTATIONS; METHYLATION; SUBGROUPS;

D O I：

10.1038/s41467-019-09140-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 met 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.

引用

页数：13

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