Histone H3 E50K remodels chromatin to confer oncogenic activity and support EMT phenotype [ATAC-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1208934 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31951252_1.fastq.gz | Fastqsanger.gz | |||
| SRR31951252_2.fastq.gz | Fastqsanger.gz | |||
| SRR31951253_1.fastq.gz | Fastqsanger.gz | |||
| SRR31951253_2.fastq.gz | Fastqsanger.gz | |||
| SRR31951254_1.fastq.gz | Fastqsanger.gz |
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Project description:Histone H3 E50K remodels chromatin to confer oncogenic activity and support EMT phenotype [Cut & Tag]
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Project description:Sequencing of human patient tumors has identified recurrent missense mutations in genes encoding core histones. We report that mutations that convert histone H3 amino acid 50 from a glutamate to a lysine (H3E50K) support an oncogenic phenotype. Expression of H3E50K is sufficient to transform human cells as evidenced by an increase in cell migration and invasion, and an increase in proliferation and clonogenicity. H3E50K also increases the invasive phenotype in the context of co-occurring BRAF mutations, which are present in patient tumors characterized by H3E50K. H3E50 lies on the globular domain surface in a region that contacts H4 within the nucleosome. We find that H3E50K selectively increases chromatin accessibility and perturbs proximal H3 post-translational modifications including H3K27me3; together these changes to chromatin dynamics dysregulate gene expression to support the epithelial to mesenchymal transition. Functional studies using S. cerevisiae reveal that, while yeast cells that express H3E50K as the sole copy of histone H3 show sensitivity to cellular stressors, including caffeine, H3E50K cells display some genetic interactions that are distinct from the characterized H3K36M oncohistone yeast model. Taken together, these data suggest that additional H3 mutations have the potential to support oncogenic activity and function through distinct mechanisms that dysregulate gene expression.
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Project description:Sequencing of human patient tumors has identified recurrent missense mutations in genes encoding core histones. We report that mutations that convert histone H3 amino acid 50 from a glutamate to a lysine (H3E50K) support an oncogenic phenotype. Expression of H3E50K is sufficient to transform human cells as evidenced by an increase in cell migration and invasion, and an increase in proliferation and clonogenicity. H3E50K also increases the invasive phenotype in the context of co-occurring BRAF mutations, which are present in patient tumors characterized by H3E50K. H3E50 lies on the globular domain surface in a region that contacts H4 within the nucleosome. We find that H3E50K selectively increases chromatin accessibility and perturbs proximal H3 post-translational modifications including H3K27me3; together these changes to chromatin dynamics dysregulate gene expression to support the epithelial to mesenchymal transition. Functional studies using S. cerevisiae reveal that, while yeast cells that express H3E50K as the sole copy of histone H3 show sensitivity to cellular stressors, including caffeine, H3E50K cells display some genetic interactions that are distinct from the characterized H3K36M oncohistone yeast model. Taken together, these data suggest that additional H3 mutations have the potential to support oncogenic activity and function through distinct mechanisms that dysregulate gene expression.
2025-01-15 | GSE286330 | GEO
Project description:Sequencing of human patient tumors has identified recurrent missense mutations in genes encoding core histones. We report that mutations that convert histone H3 amino acid 50 from a glutamate to a lysine (H3E50K) support an oncogenic phenotype. Expression of H3E50K is sufficient to transform human cells as evidenced by an increase in cell migration and invasion, and an increase in proliferation and clonogenicity. H3E50K also increases the invasive phenotype in the context of co-occurring BRAF mutations, which are present in patient tumors characterized by H3E50K. H3E50 lies on the globular domain surface in a region that contacts H4 within the nucleosome. We find that H3E50K selectively increases chromatin accessibility and perturbs proximal H3 post-translational modifications including H3K27me3; together these changes to chromatin dynamics dysregulate gene expression to support the epithelial-to-mesenchymal transition. Functional studies using Saccharomyces cerevisiae reveal that, while yeast cells that express H3E50K as the sole copy of histone H3 show sensitivity to cellular stressors, including caffeine, H3E50K cells display some genetic interactions that are distinct from the characterized H3K36M oncohistone yeast model. Taken together, these data suggest that additional H3 mutations have the potential to support oncogenic activity and function through distinct mechanisms that dysregulate gene expression.
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Project description:Histone H3 E50K mutation confers oncogenic activity and supports an EMT phenotype
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Project description:Retinal ganglion cells (RGCs) serve as the essential connection between the eye and the brain, with this connection disrupted in blinding disorders such as glaucoma. Numerous cellular mechanisms have been associated with glaucomatous neurodegeneration, and useful models for the study of glaucoma allow for the precise analysis of these degenerative phenotypes. Human pluripotent stem cells (hPSCs) serve as powerful tools for the in vitro analysis of human neurodegenerative diseases, particularly those cellular mechanisms underlying degeneration. Thus, efforts of the current study were initially focused upon the use of hPSCs with an E50K mutation in the Optineurin (OPTN) gene underlying glaucomatous neurodegeneration. CRISPR/Cas9 gene editing approaches were used to introduce the OPTN(E50K) mutation into existing lines of hPSCs, as well as the generation of isogenic control lines from existing OPTN(E50K) patient-derived hPSC lines. When grown from glaucomatous sources, hPSC-derived RGCs developed similarly to isogenic controls. Conversely, at later stages of maturation, OPTN(E50K) RGCs exhibited numerous deficits associated with a neurodegenerative phenotype, including neurite retraction, autophagy pathway disruption, apoptosis, and increased excitability. The results of this study provide an extensive analysis of the OPTN(E50K) mutation in hPSC-derived RGCs, with a number of biochemical and molecular alterations associated with functional changes to these RGCs. The opportunity now exists to further explore the precise cellular pathways leading to RGC death in glaucoma, as well as develop novel translational approaches for glaucoma including pharmacological screening and cell replacement therapies.
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Project description:Chronic hypoxia remodels the tumor microenvironment to support glioma stem cell growth [scRNAseq+Multiome]
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Project description:Sequencing of human patient tumors has identified recurrent missense mutations in genes encoding core histones. We report that mutations that convert histone H3 amino acid 50 from a glutamate to a lysine (H3E50K) support an oncogenic phenotype in human cells. Expression of H3E50K is sufficient to transform human cells as evidenced by a dramatic increase in cell migration and invasion, and a statistically significant increase in proliferation and clonogenicity. H3E50K also increases the invasive phenotype in the context of co-occurring BRAF mutations, which are present in patient tumors characterized by H3E50K. H3E50 lies on the globular domain surface in a region that contacts H4 within the nucleosome. We find that H3E50K perturbs proximal H3 post-translational modifications globally and dysregulates gene expression, activating the epithelial to mesenchymal transition. Functional studies using S. cerevisiae reveal that, while yeast cells that express H3E50K as the sole copy of histone H3 show sensitivity to cellular stressors, including caffeine, H3E50K cells display some genetic interactions that are distinct from the characterized H3K36M oncohistone yeast model. Taken together, these data suggest that additional histone H3 mutations have the potential to be oncogenic drivers and function through distinct mechanisms that dysregulate gene expression.
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