title: The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Fang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Gan
authors.affiliation: 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.
authors.forename: Jeong-Heon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Zhiquan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Riester
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota at Twin Cities, Minneapolis, MN 55455, USA.
authors.forename: Jianji
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Jinglong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Honglian
authors.initials: H
authors.lastname: Zhang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 5 Datun Road, Beijing 100101, China.
authors.forename: Na
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Bradley
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic Arizona, 13400 East Shea B., Scottsdale, AZ 85259, USA.
authors.forename: Thai H
authors.initials: TH
authors.lastname: Ho
authors.affiliation: 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.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.affiliation: Departments of Pathology and Microbiology, Pediatrics, and Orthopaedic Surgery and Rehabilitation.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Bridge
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.affiliation: 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.
authors.forename: Tamas
authors.initials: T
authors.lastname: Ordog
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota at Twin Cities, Minneapolis, MN 55455, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.affiliation: 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.
authors.forename: Andre M
authors.initials: AM
authors.lastname: Oliveira
authors.affiliation: 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.
authors.forename: Rui-Ming
authors.initials: RM
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Westendorf
authors.affiliation: 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.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D019943:Amino Acid Substitution; D001859:Bone Neoplasms / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics*; D002804:Chondroblastoma / Q000235:genetics*; D044127:Epigenesis, Genetic; D052138:Genes, Neoplasm; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000235:genetics*; D006801:Humans; D008239:Lysine / Q000235:genetics; D008745:Methylation; D009154:Mutation; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: D006657:Histones; D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human; C521636:SETD2 protein, human; D008239:Lysine