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H3.3G34W promotes growth and impedes differentiation of osteoblast-like mesenchymal progenitors in Giant Cell Tumour of Bone

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149211 | GEO | 2020/10/01

REPOSITORIES: GEO

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

Project description: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 population toward an ACTA2+ myofibroblast-like population, which secretes extracellular matrix ligands predicted to recruit and activate osteoclasts. Our findings suggest that H3.3 G34W leads to GCT by sustaining a transformed state in osteoblast-like progenitors, which promotes neoplastic growth, pathologic recruitment of giant osteoclasts, and bone destruction. SIGNIFICANCE: This study shows that H3.3 G34W drives GCT tumorigenesis through aberrant epigenetic remodeling, altering differentiation trajectories in mesenchymal progenitors. H3.3 G34W promotes in neoplastic stromal cells an osteoblast-like progenitor state that enables undue interactions with the tumor microenvironment, driving GCT pathogenesis. These epigenetic changes may be amenable to therapeutic targeting in GCT.See related commentary by Licht, p. 1794.This article is highlighted in the In This Issue feature, p. 1775.

| S-EPMC7710565 | biostudies-literature

H3.3G34W promotes growth and impedes differentiation of osteoblast-like mesenchymal progenitors in Giant Cell Tumour of Bone [RNA-Seq]

Project description:Glycine 34 to tryptophan (G34W) substitutions in H3.3 arise in ~90% of giant cell tumour of bone (GCT). Here, we show H3.3G34W is necessary for tumour formation. Profiling the epigenome, transcriptome and secreted proteome of patient samples and tumour-derived cells CRISPR/Cas9-edited for H3.3G34W shows that H3.3K36me3 loss on mutant H3.3 induces a shift of the repressive H3K27me3 mark from intergenic to genic regions, beyond areas of H3.3 deposition. This promotes the redistribution of antagonistic chromatin marks and aberrant downregulation of contractile myofibroblast-associated genes altering cell fate in mesenchymal progenitors. Single-cell transcriptomics reveals that H3.3G34W stromal cells recapitulate a neoplastic trajectory from an SPP1+ osteoblast progenitor-like population towards an ACTA2+ myofibroblast population, which secretes extracellular matrix ligands predicted to recruit and activate osteoclasts. Our findings suggest that H3.3G34W leads to GCT by sustaining a transformed state in osteoblast-like progenitors which promotes neoplastic growth, pathological recruitment of giant osteoclasts, and bone destruction.

2020-10-01 | GSE149209 | GEO

H3.3G34W promotes growth and impedes differentiation of osteoblast-like mesenchymal progenitors in Giant Cell Tumour of Bone [ChIP-Seq]

2020-10-01 | GSE149198 | GEO

H3.3G34W promotes growth and impedes differentiation of osteoblast-like mesenchymal progenitors in giant cell tumour of bone [scRNA-Seq and snRNA-Seq]

2020-10-01 | GSE149201 | GEO

H3.3G34W promotes growth and impedes differentiation of osteoblast-like mesenchymal progenitors in Giant Cell Tumour of Bone

Project description:H3.3G34W promotes growth and impedes differentiation of osteoblast-like mesenchymal progenitors in Giant Cell Tumour of Bone

| PRJNA627670 | ENA

H3.3G34W promotes growth and impedes differentiation of osteoblast-like mesenchymal progenitors in Giant Cell Tumour of Bone [ChIP-Seq]

Project description:H3.3G34W promotes growth and impedes differentiation of osteoblast-like mesenchymal progenitors in Giant Cell Tumour of Bone [ChIP-Seq]

| PRJNA627645 | ENA

H3.3G34W promotes growth and impedes differentiation of osteoblast-like mesenchymal progenitors in Giant Cell Tumour of Bone [RNA-Seq]

Project description:H3.3G34W promotes growth and impedes differentiation of osteoblast-like mesenchymal progenitors in Giant Cell Tumour of Bone [RNA-Seq]

| PRJNA627673 | ENA

Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation.

Project description:Postnatal bone marrow houses mesenchymal progenitor cells that are osteoblast precursors. These cells have established therapeutic potential, but they are difficult to maintain and expand in vitro, presumably because little is known about the mechanisms controlling their fate decisions. To investigate the potential role of Notch signaling in osteoblastogenesis, we used conditional alleles to genetically remove components of the Notch signaling system during skeletal development. We found that disruption of Notch signaling in the limb skeletogenic mesenchyme markedly increased trabecular bone mass in adolescent mice. Notably, mesenchymal progenitors were undetectable in the bone marrow of mice with high bone mass. As a result, these mice developed severe osteopenia as they aged. Moreover, Notch signaling seemed to inhibit osteoblast differentiation through Hes or Hey proteins, which diminished Runx2 transcriptional activity via physical interaction. These results support a model wherein Notch signaling in bone marrow normally acts to maintain a pool of mesenchymal progenitors by suppressing osteoblast differentiation. Thus, mesenchymal progenitors may be expanded in vitro by activating the Notch pathway, whereas bone formation in vivo may be enhanced by transiently suppressing this pathway.

| S-EPMC2740725 | biostudies-literature

H3.3G34W promotes growth and impedes differentiation of osteoblast-like mesenchymal progenitors in giant cell tumour of bone [scRNA-Seq and snRNA-Seq]

Project description:H3.3G34W promotes growth and impedes differentiation of osteoblast-like mesenchymal progenitors in giant cell tumour of bone [scRNA-Seq and snRNA-Seq]

| PRJNA627656 | ENA

Gs? enhances commitment of mesenchymal progenitors to the osteoblast lineage but restrains osteoblast differentiation in mice.

Project description:The heterotrimeric G protein subunit Gs? stimulates cAMP-dependent signaling downstream of G protein-coupled receptors. In this study, we set out to determine the role of Gs? signaling in cells of the early osteoblast lineage in vivo by conditionally deleting Gs? from osterix-expressing cells. This led to severe osteoporosis with fractures at birth, a phenotype that was found to be the consequence of impaired bone formation rather than increased resorption. Osteoblast number was markedly decreased and osteogenic differentiation was accelerated, resulting in the formation of woven bone. Rapid differentiation of mature osteoblasts into matrix-embedded osteocytes likely contributed to depletion of the osteoblast pool. In addition, the number of committed osteoblast progenitors was diminished in both bone marrow stromal cells (BMSCs) and calvarial cells of mutant mice. In the absence of Gs?, expression of sclerostin and dickkopf1 (Dkk1), inhibitors of canonical Wnt signaling, was markedly increased; this was accompanied by reduced Wnt signaling in the osteoblast lineage. In summary, we have shown that Gs? regulates bone formation by at least two distinct mechanisms: facilitating the commitment of mesenchymal progenitors to the osteoblast lineage in association with enhanced Wnt signaling; and restraining the differentiation of committed osteoblasts to enable production of bone of optimal mass, quality, and strength.

| S-EPMC3163961 | biostudies-literature

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