Oncohistones and their molecular function

Mutated histones have raised a lot of interest in the cancer research community due to their ability to alter the epigenomic landscape. A frequently mutated, cancer-associated histone is the non-canonical histone variant H3.3. In contrast to canonical H3.1 and H3.2, the incorporation of histone variant H3.3 is replication independent and its turnover occurs throughout the cell cycle. Deposition occurs either via the HIRA chaperone at sites of gene activation or through ATRX-DAXX into heterochromatic regions and the silent allele of imprinted genes. While two human genes, H3F3A and H3F3B, encode for an identical H3.3 protein, oncogenic mutations occur gene-specifically in different tumor types. So far, lysine-27-to-methionine (H3.3-K27M) and glycine-to-arginine or valine substitution (H3.3-G34R/V) in gliomas, as well as glycine-34-to-tryptophan or leucine (H3.3-G34W/L) substitutions in giant cell tumor of bone (GCTB) have been described, all due to mutations in H3F3A. For H3F3B, mutations leading to glycine-36-to-methionine (H3.3-K36M) substitution were reported in chondroblastomas.

Model of GCTB tumorigenesis
© Pavlo Lutsik, DKFZ

We are interested in the analysis of H3.3-G34W/L mutations in giant cell tumor of bone (GCTB).

The H3F3A mutation encoding H3.3-G34W occurs in osteoblastic precursor cells (MSCs) and leads to alterations in osteogenic differentiation. We postulate that epigenetic differences between H3.3 WT and H3.3 MUT stromal cells are the result of analyzing cells at different differentiation stages and direct effects of the mutated histones (Lutsik et al., in press).

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