title: Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape.
abstract: Several types of pediatric cancers reportedly contain high-frequency missense mutations in histone H3, yet the underlying oncogenic mechanism remains poorly characterized. Here we report that the H3 lysine 36-to-methionine (H3K36M) mutation impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma in vivo. H3K36M mutant nucleosomes inhibit the enzymatic activities of several H3K36 methyltransferases. Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient to phenocopy the H3K36M mutation. After the loss of H3K36 methylation, a genome-wide gain in H3K27 methylation leads to a redistribution of polycomb repressive complex 1 and de-repression of its target genes known to block mesenchymal differentiation. Our findings are mirrored in human undifferentiated sarcomas in which novel K36M/I mutations in H3.1 are identified.
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Lu
authors.affiliation: Epigenetics Theme, Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USA. Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715, USA.
authors.forename: Siddhant U
authors.initials: SU
authors.lastname: Jain
authors.affiliation: Epigenetics Theme, Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USA. Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715, USA.
authors.forename: Dominik
authors.initials: D
authors.lastname: Hoelper
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec H3Z 2Z3, Canada.
authors.forename: Denise
authors.initials: D
authors.lastname: Bechet
authors.affiliation: Epigenetics Program and Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Rosalynn C
authors.initials: RC
authors.lastname: Molden
authors.affiliation: Human Oncology and Pathogenesis Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Leili
authors.initials: L
authors.lastname: Ran
authors.affiliation: Human Oncology and Pathogenesis Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Devan
authors.initials: D
authors.lastname: Murphy
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Venneti
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Meera
authors.initials: M
authors.lastname: Hameed
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Pawel
authors.affiliation: University Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. Department of Surgical Oncology and Division of Orthopedic Surgery, Princess Margaret Hospital, University of Toronto, Toronto, Ontario M5T 2M9, Canada.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Wunder
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Brendan C
authors.initials: BC
authors.lastname: Dickson
authors.affiliation: Epigenetics Theme, Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USA. Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715, USA.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Lundgren
authors.affiliation: Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Krupa S
authors.initials: KS
authors.lastname: Jani
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec H3Z 2Z3, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: De Jay
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec H3Z 2Z3, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Papillon-Cavanagh
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. The Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.affiliation: Department of Medical Genetics and Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Sawyer
authors.affiliation: Department of Medical Genetics and Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Grynspan
authors.affiliation: Division of Orthopaedic Surgery, Montreal General Hospital, McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Turcotte
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec H3Z 2Z3, Canada.
authors.forename: Javad
authors.initials: J
authors.lastname: Nadaf
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec H3Z 2Z3, Canada.
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Fahiminiyah
authors.affiliation: Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Tom W
authors.initials: TW
authors.lastname: Muir
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec H3Z 2Z3, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.affiliation: Human Oncology and Pathogenesis Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Chi
authors.affiliation: Epigenetics Program and Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. plewis@discovery.wisc.edu nada.jabado@mcgill.ca alliscd@rockefeller.edu.
authors.forename: C David
authors.initials: CD
authors.lastname: Allis
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec H3Z 2Z3, Canada. Department of Pediatrics, McGill University, Montreal, Quebec H3Z 2Z3, Canada. plewis@discovery.wisc.edu nada.jabado@mcgill.ca alliscd@rockefeller.edu.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: Epigenetics Theme, Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USA. Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715, USA. plewis@discovery.wisc.edu nada.jabado@mcgill.ca alliscd@rockefeller.edu.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Lewis
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D002804:Chondroblastoma / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D008715:Methionine / Q000235:genetics; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D020125:Mutation, Missense; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009707:Nucleosomes / Q000235:genetics; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics* / Q000473:pathology
chemical_list: D006657:Histones; D009707:Nucleosomes; D008715:Methionine; D008780:Methyltransferases; D063150:Polycomb Repressive Complex 1; D008239:Lysine