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

Lutsik P, Baude A, Mancarella D, Öz S, Kühn A, Toth R, Hey J, Toprak UH, Lim J, Nguyen VH, Jiang C, Mayakonda A, Hartmann M, Rosemann F, Breuer K, Vonficht D, Grünschläger F, Lee S, Schuhmacher MK, Kusevic D, Jauch A, Weichenhan D, Zustin J, Schlesner M, Haas S, Park JH, Park YJ, Oppermann U, Jeltsch A, Haller F, Fellenberg J, Lindroth AM, Plass C (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 11

Article Number: 5414

Journal Issue: 1

DOI: 10.1038/s41467-020-18955-y

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.

Authors with CRIS profile

Florian Haller Professur für Diagnostische Molekularpathologie

Involved external institutions

Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Universität Stuttgart DE Germany (DE) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) National Cancer Center (NCC) / 국립암센터 KR Korea, Republic of (KR) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Universitätsklinikum Heidelberg DE Germany (DE) University of Oxford GB United Kingdom (GB) Ewha Womans University / 이화여자대학교 KR Korea, Republic of (KR)

How to cite

APA:

Lutsik, P., Baude, A., Mancarella, D., Öz, S., Kühn, A., Toth, R.,... Plass, C. (2020). Globally altered epigenetic landscape and delayed osteogenic differentiation in H3.3-G34W-mutant giant cell tumor of bone. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-18955-y

MLA:

Lutsik, Pavlo, et al. "Globally altered epigenetic landscape and delayed osteogenic differentiation in H3.3-G34W-mutant giant cell tumor of bone." Nature Communications 11.1 (2020).

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