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Globally altered epigenetic landscape and delayed osteogenic differentiation in H3.3-G34W-mutant giant cell tumor of bone

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Item Type:Article
Title:Globally altered epigenetic landscape and delayed osteogenic differentiation in H3.3-G34W-mutant giant cell tumor of bone
Creators Name:Lutsik, P. and Baude, A. and Mancarella, D. and Öz, S. and Kühn, A. and Toth, R. and Hey, J. and Toprak, U.H. and Lim, J. and Nguyen, V.H. and Jiang, C. and Mayakonda, A. and Hartmann, M. and Rosemann, F. and Breuer, K. and Vonficht, D. and Grünschläger, F. and Lee, S. and Schuhmacher, M.K. and Kusevic, D. and Jauch, A. and Weichenhan, D. and Zustin, J. and Schlesner, M. and Haas, S. and Park, J.H. and Park, Y.J. and Oppermann, U. and Jeltsch, A. and Haller, F. and Fellenberg, J. and Lindroth, A.M. and Plass, C.
Abstract:The neoplastic stromal cells of giant cell tumor of bone (GCTB) carry a mutation in H3F3A, leading to a mutant histone variant, H3.3-G34W, as a sole recurrent genetic alteration. We show that in patient-derived stromal cells H3.3-G34W is incorporated into the chromatin and associates with massive epigenetic alterations on the DNA methylation, chromatin accessibility and histone modification level, that can be partially recapitulated in an orthogonal cell line system by the introduction of H3.3-G34W. These epigenetic alterations affect mainly heterochromatic and bivalent regions and provide possible explanations for the genomic instability, as well as the osteolytic phenotype of GCTB. The mutation occurs in differentiating mesenchymal stem cells and associates with an impaired osteogenic differentiation. We propose that the observed epigenetic alterations reflect distinct differentiation stages of H3.3 WT and H3.3 MUT stromal cells and add to H3.3-G34W-associated changes.
Keywords:Bone Neoplasms, DNA Methylation, Epigenomics, Genetic Epigenesis, Giant Cell Tumor of Bone, Histones, Missense Mutation, Osteogenesis
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:5414
Date:27 October 2020
Official Publication:https://doi.org/10.1038/s41467-020-18955-y
PubMed:View item in PubMed

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