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.
Highlights
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
H3.3, including G34W, inhibit the activity of the histone methyltransferase SET domain containing 2 (SETD2), which is responsible for H3K36me[3], in cis[16]
Cell type differences were ruled out by flow cytometric analyses which revealed a high expression of mesenchymal stem cells (MSC) markers and low expression of hematopoietic markers in both H3.3 WT and H3.3 MUT cell lines, suggesting that both are of mesenchymal origin (Supplementary Fig. 1d)
Summary
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. GCTB is a rare locally aggressive bone neoplasm that typically affects the meta-epiphyseal regions of long bones in young adults[17] These tumors consist of three major cell types: stromal cells originating from mesenchymal stem cells (MSC), multinuclear giant cells and mononuclear histiocytic cells[18]. Our findings collectively suggest that the single-residue alteration of H3.3 induces epigenomic changes with implications for the development of stromal cells and the tumorigenic process
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