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

Dong Fang; Haiyun Gan; Jeong-Heon Lee; Jing Han; Zhiquan Wang; Scott M Riester; Long Jin; Jianji Chen; Hui Zhou; Jinglong Wang; Honglian Zhang; Na Yang; Elizabeth W Bradley; Thai H Ho; Brian P Rubin; Julia A Bridge; Stephen N Thibodeau; Tamas Ordog; Yue Chen; Andre J van Wijnen; Andre M Oliveira; Rui-Ming Xu; Jennifer J Westendorf; Zhiguo Zhang

doi:10.1126/science.aae0065

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

Science. 2016 Jun 10;352(6291):1344-8. doi: 10.1126/science.aae0065. Epub 2016 May 26.

Authors

Dong Fang¹, Haiyun Gan¹, Jeong-Heon Lee², Jing Han¹, Zhiquan Wang¹, Scott M Riester³, Long Jin³, Jianji Chen⁴, Hui Zhou¹, Jinglong Wang⁵, Honglian Zhang¹, Na Yang⁶, Elizabeth W Bradley³, Thai H Ho⁷, Brian P Rubin⁸, Julia A Bridge⁹, Stephen N Thibodeau¹⁰, Tamas Ordog¹¹, Yue Chen⁴, Andre J van Wijnen¹², Andre M Oliveira¹³, Rui-Ming Xu⁵, Jennifer J Westendorf¹², Zhiguo Zhang¹⁴

Affiliations

¹ Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
² Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. Epigenomics Program, Center of Individualized Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
³ Department of Orthopedic Surgery, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
⁴ Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota at Twin Cities, Minneapolis, MN 55455, USA.
⁵ National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 5 Datun Road, Beijing 100101, China. University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
⁶ National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 5 Datun Road, Beijing 100101, China.
⁷ Division of Hematology/Oncology, Mayo Clinic Arizona, 13400 East Shea B., Scottsdale, AZ 85259, USA.
⁸ Robert J. Tomsich Pathology and Laboratory Medicine Institute and Department of Cancer Biology, Cleveland Clinic and Lerner Research Institute, L2 9500 Euclid Avenue, Cleveland, OH 44195, USA.
⁹ Departments of Pathology and Microbiology, Pediatrics, and Orthopaedic Surgery and Rehabilitation.
¹⁰ Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
¹¹ Epigenomics Program, Center of Individualized Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. Department of Physiology and Biomedical Engineering, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. Interdisciplinary Health Science Initiative, 1110 Micro and Nanotechnology Laboratory, M/C 249, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
¹² Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. Department of Orthopedic Surgery, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
¹³ Department of Orthopedic Surgery, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
¹⁴ Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. Epigenomics Program, Center of Individualized Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. zhang.zhiguo@mayo.edu.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Substitution
Bone Neoplasms / genetics*
Carcinogenesis / genetics*
Chondroblastoma / genetics*
Epigenesis, Genetic*
Genes, Neoplasm*
Histone-Lysine N-Methyltransferase / metabolism
Histones / genetics*
Humans
Lysine / genetics
Methylation
Mutation
Repressor Proteins / metabolism

Substances

Histones
Repressor Proteins
Histone-Lysine N-Methyltransferase
NSD2 protein, human
SETD2 protein, human
Lysine

Abstract

Publication types

MeSH terms

Substances

Grants and funding