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

Title
Globally altered epigenetic landscape and delayed osteogenic differentiation in H3.3-G34W-mutant giant cell tumor of bone
Authors
Lutsik, PavloBaude, AnnikaMancarella, DanielaOz, SiminKuhn, AlexanderToth, RekaHey, JoschkaToprak, Umut H.Lim, JinyeongViet Ha NguyenJiang, ChaoMayakonda, AnandHartmann, MarkRosemann, FelixBreuer, KerstenVonficht, DominikGruenschlaeger, FlorianLee, SumanSchuhmacher, Maren KirstinKusevic, DenisJauch, AnnaWeichenhan, DieterZustin, JozefSchlesner, MatthiasHaas, SimonPark, Joo HyunPark, Yoon JungOppermann, UdoJeltsch, AlbertHaller, FlorianFellenberg, JoergLindroth, Anders M.Plass, Christoph
Ewha Authors
박윤정
SCOPUS Author ID
박윤정scopus
Issue Date
2020
Journal Title
NATURE COMMUNICATIONS
ISSN
2041-1723JCR Link
Citation
NATURE COMMUNICATIONS vol. 11, no. 1
Publisher
NATURE RESEARCH
Indexed
SCIE; SCOPUS WOS scopus
Document Type
Article
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. The histone variant mutation H3.3-G34W occurs in the majority of giant cell tumor of bone (GCTB). By profiling patient-derived GCTB tumor cells, the authors show that this mutation associates with epigenetic alterations in heterochromatic and bivalent regions that contribute to an impaired osteogenic differentiation and the osteolytic phenotype of GCTB.
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DOI
10.1038/s41467-020-18955-y
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신산업융합대학 > 식품영양학과 > Journal papers
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