The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas

被引：197

作者：

Fang, Dong ^{[1
]}

Gan, Haiyun ^{[1
]}

Lee, Jeong-Heon ^{[1
,2
]}

Han, Jing ^{[1
]}

Wang, Zhiquan ^{[1
]}

Riester, Scott M. ^{[3
]}

Jin, Long ^{[3
]}

Chen, Jianji ^{[4
]}

Zhou, Hui ^{[1
]}

Wang, Jinglong ^{[5
,6
]}

Zhang, Honglian ^{[1
]}

Yang, Na ^{[5
]}

Bradley, Elizabeth W. ^{[3
]}

Ho, Thai H. ^{[7
]}

Rubin, Brian P. ^{[8
,9
,10
]}

Bridge, Julia A. ^{[11
,12
,13
]}

Thibodeau, Stephen N. ^{[14
]}

Ordog, Tamas ^{[2
,15
,16
]}

Chen, Yue ^{[4
]}

van Wijnen, Andre J. ^{[1
,3
]}

Oliveira, Andre M. ^{[3
,14
]}

Xu, Rui-Ming ^{[5
,6
]}

Westendorf, Jennifer J. ^{[1
,3
]}

Zhang, Zhiguo ^{[1
,2
]}

机构：

[1] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, 200 First St SW, Rochester, MN 55905 USA

[2] Mayo Clin, Coll Med, Ctr Individualized Med, Epigen Program, 200 First St SW, Rochester, MN 55905 USA

[3] Mayo Clin, Coll Med, Dept Orthoped Surg, 200 First St SW, Rochester, MN 55905 USA

[4] Univ Minnesota Twin Cities, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA

[5] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, 5 Datun Rd, Beijing 100101, Peoples R China

[6] Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China

[7] Mayo Clin Arizona, Div Hematol Oncol, 13400 East Shea B, Scottsdale, AZ 85259 USA

[8] Cleveland Clin, Robert J Tomsich Pathol & Lab Med Inst, L2 9500 Euclid Ave, Cleveland, OH 44195 USA

[9] Cleveland Clin, Dept Canc Biol, L2 9500 Euclid Ave, Cleveland, OH 44195 USA

[10] Cleveland Clin, Lerner Res Inst, L2 9500 Euclid Ave, Cleveland, OH 44195 USA

[11] Mayo Clin, Coll Med, Dept Pathol & Microbiol, 200 First St SW, Rochester, MN 55905 USA

[12] Mayo Clin, Coll Med, Dept Pediat, 200 First St SW, Rochester, MN 55905 USA

[13] Mayo Clin, Coll Med, Dept Orthopaed Surg & Rehabil, 200 First St SW, Rochester, MN 55905 USA

[14] Mayo Clin, Coll Med, Dept Lab Med & Pathol, 200 First St SW, Rochester, MN 55905 USA

[15] Mayo Clin, Coll Med, Div Gastroenterol & Hepatol, Dept Physiol & Biomed Engn, 200 First St SW, Rochester, MN 55905 USA

[16] Univ Illinois, Interdisciplinary Hlth Sci Initiat, Micro & Nanotechnol Lab 1110, M-C 249, Urbana, IL 61801 USA

来源：

SCIENCE | 2016年 / 352卷 / 6291期

关键词：

H3K36; METHYLATION; VARIANT H3.3; REPAIR; ACTIVATION; EXPRESSION; REGIONS; BONE;

D O I：

10.1126/science.aae0065

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：

More than 90% of chondroblastomas contain a heterozygous mutation replacing lysine-36 with methionine-36 (K36M) in the histone H3 variant H3.3. Here we show that H3K36 methylation is reduced globally in human chondroblastomas and in chondrocytes harboring the same genetic mutation, due to inhibition of at least two H3K36 methyltransferases, MMSET and SETD2, by the H3.3K36M mutant proteins. Genes with altered expression as well as H3K36 di- and trimethylation in H3.3K36M cells are enriched in cancer pathways. In addition, H3.3K36M chondrocytes exhibit several hallmarks of cancer cells, including increased ability to form colonies, resistance to apoptosis, and defects in differentiation. Thus, H3.3K36M proteins reprogram the H3K36 methylation landscape and contribute to tumorigenesis, in part through altering the expression of cancer-associated genes.

引用

页码：1344 / 1348

页数：5

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