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

Joo Hyun Park, Suman Lee, Maren Kirstin Schuhmacher, Denis Kusevic, Anna Jauch, Dieter Weichenhan, Jozef Zustin, Matthias Schlesner, Simon Haas, Florian Grünschläger, Yoon Jung Park, Udo Oppermann, Albert Jeltsch, Florian Haller, Jörg Fellenberg, Anders M Lindroth, Christoph Plass, Pavlo Lutsik, Dominik Vonficht, Kersten Breuer, Felix Rosemann, Mark Hartmann, Anand Mayakonda, Chao Jiang, Viet Ha Nguyen, Jinyeong Lim, Umut H Toprak, Joschka Hey, Reka Toth, Alexander Kühn, Simin Öz, Daniela Mancarella, Annika Baude

Journal: Nature communications 2020;11(1):5414

PMID: 33110075

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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.

Address: Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Faculty of Biosciences, Ruprecht Karl University of Heidelberg, Im Neuenheimer Feld 234, 69120, Heidelberg, Germany.; Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Graduate School of Cancer Science and Policy, Cancer Biomedical Science, National Cancer Center, Goyang-si, Gyeonggi-do, 10408, Republic of Korea, Republic of Korea.; Botnar Research Centre, Oxford NIHR BRC, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7LD, UK.; Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) & German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Heidelberg Institute for Stem Cell Technology and Experimental Medicine-HI-STEM gGmbH, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.; Institute of Human Genetics, Ruprecht Karl University of Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.; Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251, Hamburg, Germany.; Department of Nutritional Science and Food Management, Ewha Womans University, 52 Ewhayeodae-gil, Daehyeon-dong, Seodaemun-gu, Seoul, 03760, Republic of Korea.; FRIAS-Freiburg Institute of Advanced Studies, Albert Ludwig University of Freiburg, Alberstrasse 19, 79104, Freiburg, Germany.; Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nürnberg, Krankenstrasse 8, 91054, Erlangen, Germany.; Department of Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg, Ruprecht Karl University of Heidelberg, Schlierbacher Landstrasse 200a, 69118, Heidelberg, Germany.; Graduate School of Cancer Science and Policy, Cancer Biomedical Science, National Cancer Center, Goyang-si, Gyeonggi-do, 10408, Republic of Korea, Republic of Korea. [email protected].; Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. [email protected].; German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany. [email protected].

DOI: 10.1038/s41467-020-18955-y

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MeSH Terms: Bone Neoplasms, DNA Methylation, Epigenesis, Genetic, Epigenomics, Giant Cell Tumor of Bone, Histones, Humans, Mutation, Missense, Osteogenesis