H3.3 G34W Promotes Growth and Impedes Differentiation of Osteoblast-Like Mesenchymal Progenitors in Giant Cell Tumor of Bone.

ABSTRACT: Glycine 34-to-tryptophan (G34W) substitutions in H3.3 arise in approximately 90% of giant cell tumor of bone (GCT). Here, we show H3.3 G34W is necessary for tumor formation. By profiling the epigenome, transcriptome, and secreted proteome of patient samples and tumor-derived cells CRISPR-Cas9-edited for H3.3 G34W, we show that H3.3K36me3 loss on mutant H3.3 alters the deposition of the repressive H3K27me3 mark from intergenic to genic regions, beyond areas of H3.3 deposition. This promotes redistribution of other chromatin marks and aberrant transcription, altering cell fate in mesenchymal progenitors and hindering differentiation. Single-cell transcriptomics reveals that H3.3 G34W stromal cells recapitulate a neoplastic trajectory from a SPP1⁺ osteoblast-like progenitor

SUBMITTER: Khazaei S 

PROVIDER: S-EPMC7710565 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature