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Phenotypic and Functional Characterization of Oncohistone Mutations in Breast Cancers [RNA-seq]

ABSTRACT: Phenotypic and Functional Characterization of Oncohistone Mutations in Breast Cancers [RNA-seq]

PROVIDER: PRJNA1256248 | ENA |

REPOSITORIES: ENA

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Phenotypic and Functional Characterization of Oncohistone Mutations in Breast Cancers

Project description:Phenotypic and Functional Characterization of Oncohistone Mutations in Breast Cancers

| PRJNA1257087 | ENA

Phenotypic and Functional Characterization of Oncohistone Mutations in Breast Cancers [RNA-seq]

Project description:Although mutations in genes encoding histones display a similar prevalence to that of some other somatic mutations in cancer, the underlying mechanisms by which histone mutations drive tumorigenesis have not been fully explored. Herein, we curated missense mutations occurring in core histone genes in breast cancers using data from MSK-IMPACT and cBioPortal to identify high frequency breast cancer-associated histone gene mutations. We characterized 17 high frequency oncohistone mutations in H2A H2B, and H3 that are enriched in breast cancer samples and occurred at glutamate (E), aspartate (D), serine (S), and arginine (R) residues. Many of these mutants co-occur with PIK3CA mutations in breast cancer samples. The oncohistone mutants were expressed in MCF-7 breast cancer cells or MCF10A mammary epithelial cells and screened for effects on oncogenic phenotypes in a variety of cell- and tumor-based assays (i.e., proliferation, migration, invasion, competitive outgrowth, transformation). In addition, we examined the effects of selected mutants on DNA damage, gene expression, and posttranslational modification of histones (e.g., acetylation, phosphorylation, methylation, ADP-ribosylation). Our results indicate that the collection of oncohistone mutants that we screened have varying phenotypic and functional effects. Some can promote cancer-related phenotypes and may act as potential cancer drivers, with H2B-E76K/Q, H3-E97K, and H3-E105K eliciting strong cancer phenotypes. These observations can be used as a resource to connect biological and molecular outcomes to oncohistones in breast cancers.

2025-07-30 | GSE295718 | GEO

Phenotypic and Functional Characterization of Oncohistone Mutations in Breast Cancers

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-07-30 | GSE295988 | GEO

Oncohistone mutations occur at functional sites of regulatory ADP-ribosylation: the role of oncohistone mutations in transcriptional regulation

Project description:Oncohistone mutations occur at functional sites of regulatory ADP-ribosylation: the role of oncohistone mutations in transcriptional regulation

| PRJNA748361 | ENA

Oncohistone mutations occur at functional sites of regulatory ADP-ribosylation: the role of oncohistone mutations in transcriptional regulation [ChIP-Seq]

Project description:Oncohistone mutations occur at functional sites of regulatory ADP-ribosylation: the role of oncohistone mutations in transcriptional regulation [ChIP-Seq]

| PRJNA748364 | ENA

Oncohistone mutations occur at functional sites of regulatory ADP-ribosylation: the role of oncohistone mutations in transcriptional regulation [RNA-Seq]

Project description:Oncohistone mutations occur at functional sites of regulatory ADP-ribosylation: the role of oncohistone mutations in transcriptional regulation [RNA-Seq]

| PRJNA748367 | ENA

Oncohistone mutations occur at functional sites of regulatory ADP-ribosylation: the role of oncohistone mutations in transcriptional regulation [ATAC-Seq]

Project description:Oncohistone mutations occur at functional sites of regulatory ADP-ribosylation: the role of oncohistone mutations in transcriptional regulation [ATAC-Seq]

| PRJNA748363 | ENA

Inhibition of Histone H3-H4 Chaperone Pathways Rescues Dysfunctional Oncohistone H2B

Project description:Oncohistone mutations are crucial drivers for tumorigenesis, but how a living organism responds to and governs the loss-of-function oncohistone remains unclear. Here, we generated a histone H2B triple knockout (3KO) strain in Caenorhabditis elegans, which decreased the embryonic H2B level, disrupted cell divisions, and caused animal sterility. Our genetic screens identified mutations defective in a histone H3-H4 chaperone UNC-85 as suppressors that recovered H2B 3KO fertility. We found that unc-85 mutations reduced chromatin H3-H4 levels and that inhibiting other H3-H4 chaperones or H3-H4 histones also rescued H2B 3KO sterility. The oncohistone H2BE76K mutation disrupts the H2B-H4 interface and causes nucleosome instability, and we showed that blocking H3-H4 chaperones restored cell division defects in C. elegans or human cells carrying H2BE76K. Thus, our results indicate that reducing chromatin H3-H4 rescues H2B loss and suggest that inhibiting H3-H4 chaperones may be a therapeutic strategy to treat cancers resulting from loss-of-function H2B oncohistone.

2022-04-03 | GSE185582 | GEO

The H3.3K27M oncohistone antagonizes reprogramming in Drosophila

Project description:Development proceeds by the activation of genes by transcription factors and the inactivation of others by chromatin-mediated gene silencing. In some cases development can be reversed or redirected by mis-expression of master regulator transcription factors. This must involve the activation of previously silenced genes, and such developmental aberrations are thought to underlie a variety of cancers. Here, we express the wing-specific Vestigial master regulator to reprogram the developing eye, and test the role of silencing in reprogramming using an H3.3K27M oncohistone mutation that dominantly inhibits histone H3K27 trimethylation. We find that expression of the oncohistone blocks eye-to-wing reprogramming. CUT&Tag chromatin profiling of mutant tissues shows that H3K27me3 domains are globally reduced with oncohistone expression, suggesting that previous developmental programs must be silenced for effective transformation. Strikingly, mis-expressed Vg and H3.3K27M synergize to stimulate overgrowth of eye tissue, a phenotype that resembles that of mutations in Polycomb Repressive Complex 1 components. Our results imply that growth dysregulation can result from the simple combination of crippled silencing and transcription factor mis-expression, an effect that may explain the origins of oncohistone-bearing cancers.

2021-06-15 | GSE161919 | GEO

The expanding landscape of 'oncohistone' mutations in human cancers.

Project description:Mutations in epigenetic pathways are common oncogenic drivers. Histones, the fundamental substrates for chromatin-modifying and remodelling enzymes, are mutated in tumours including gliomas, sarcomas, head and neck cancers, and carcinosarcomas. Classical 'oncohistone' mutations occur in the N-terminal tail of histone H3 and affect the function of polycomb repressor complexes 1 and 2 (PRC1 and PRC2). However, the prevalence and function of histone mutations in other tumour contexts is unknown. Here we show that somatic histone mutations occur in approximately 4% (at a conservative estimate) of diverse tumour types and in crucial regions of histone proteins. Mutations occur in all four core histones, in both the N-terminal tails and globular histone fold domains, and at or near residues that contain important post-translational modifications. Many globular domain mutations are homologous to yeast mutants that abrogate the need for SWI/SNF function, occur in the key regulatory 'acidic patch' of histones H2A and H2B, or are predicted to disrupt the H2B-H4 interface. The histone mutation dataset and the hypotheses presented here on the effect of the mutations on important chromatin functions should serve as a resource and starting point for the chromatin and cancer biology fields in exploring an expanding role of histone mutations in cancer.

| S-EPMC6512987 | biostudies-literature

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