title: Mutant IDH1 Dysregulates the Differentiation of Mesenchymal Stem Cells in Association with Gene-Specific Histone Modifications to Cartilage- and Bone-Related Genes.
abstract: Somatic mutations in the isocitrate dehydrogenase (IDH)1/2 genes endow encoding proteins with neomorphic activity to produce the potential oncometabolite, 2-hydroxyglutarate (2-HG), which induces the hypermethylation of histones and DNA. The incidence of IDH1/2 mutations in cartilaginous tumors was previously shown to be the highest among various types of tumors, except for those in the central nervous system. Mutations have been detected in both benign (enchondromas) and malignant (chondrosarcomas) types of cartilaginous tumors, whereas they have rarely been found in other mesenchymal tumors such as osteosarcomas. To address this unique tumor specificity, we herein examined the effects of IDH1 R132C, which is the most prevalent mutant in cartilaginous tumors, on the differentiation properties of human mesenchymal stem cells (hMSCs). The induction of the IDH1 R132C gene into MSCs markedly increased the amount of 2-HG and up-regulated global histone methylation. The induction of IDH1 R132C promoted the chondrogenic differentiation of hMSCs by enhancing the expression of SOX9 and COL2A1 genes in association with an increase in the active mark (H3K4me3), but disrupted cartilage matrix formation. On the other hand, IDH1 R132C inhibited expression of the ALPL gene in association with an increase in the repressive mark (H3K9me3), and subsequently inhibited the osteogenic properties of hMSCs and human osteosarcoma cells. Since osteogenic properties are an indispensable feature for the diagnosis of osteosarcoma, the inhibitory effects of IDH1 R132C on osteogenic properties may contribute to the lack of osteosarcomas with the IDH1 R132C mutation. These results suggested that IDH1 R132C contributed to the formation of cartilaginous tumors by dysregulating the chondrogenic and osteogenic differentiation of hMSCs via gene-specific histone modulation.
authors.affiliation: Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Hassan
authors.initials: H
authors.lastname: Elalaf
authors.affiliation: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan; Life Science Research Center, Shimadzu Cooperation, Kyoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Sakura
authors.initials: S
authors.lastname: Tamaki
authors.affiliation: Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Hineno
authors.affiliation: Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan; Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yamaguchi University, Ube, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Matsunaga
authors.affiliation: Department of Reprogramming Sciences, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Knut
authors.initials: K
authors.lastname: Woltjen
authors.affiliation: Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Sanae
authors.initials: S
authors.lastname: Nagata
authors.affiliation: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ikeya
authors.affiliation: Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Okamoto
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Matsuda
authors.affiliation: Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan; Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan; Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Toguchida
mesh_terms: D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D002813:Chondrosarcoma / Q000201:enzymology / Q000235:genetics; D004687:Enchondromatosis / Q000201:enzymology / Q000235:genetics; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006657:Histones / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D059630:Mesenchymal Stem Cells / Q000201:enzymology* / Q000502:physiology; D008745:Methylation; D020125:Mutation, Missense; D012516:Osteosarcoma / Q000201:enzymology / Q000235:genetics; D011499:Protein Processing, Post-Translational
chemical_list: D006657:Histones; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human