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Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation

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

ORGANISM(S): Mus musculus

PROVIDER: GSE239638 | GEO | 2024/04/29

REPOSITORIES: GEO

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Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation.

Project description:Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants is exclusively observed on the minor fraction of histone tails harboring the mutations, the same mutants recurrently disrupt broad H3K27me3 domains in the chromatin context, including near developmentally regulated promoters. H3K27me3 loss leads to de-repression of differentiation pathways, with concordant effects between H3R2 and H3R26 mutants despite different proximity to the PRC2 substrate, H3K27. Functionally, H3R26C-expressing mesenchymal progenitor cells and murine embryonic stem cell-derived teratomas demonstrate impaired differentiation. Collectively, these data show that cancer-associated H3 N-terminal arginine mutations reduce PRC2 activity and disrupt chromatin-dependent developmental functions, a cancer-relevant phenotype.

| S-EPMC11183192 | biostudies-literature

Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation

Project description:Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation. Middle down analysis of histone H3 WT or mutant

2023-07-27 | MSV000092535 | MassIVE

Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation [scRNA-Seq]

Project description:Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants was exclusively observed on the minor fraction of histone tails harboring the mutations, the same mutants recurrently disrupted broad H3K27me3 domains in the chromatin context, including near developmentally regulated promoters. H3K27me3 loss led to de-repression of differentiation pathways, with concordant effects between H3R2 and H3R26 mutants despite different proximity to the PRC2 substrate, H3K27. Functionally, H3R26C-expressing mesenchymal progenitor cells and murine embryonic stem cell-derived teratomas demonstrated impaired differentiation. Collectively, these data show that cancer-associated H3 N-terminal arginine mutations reduce PRC2 activity and disrupt chromatin-dependent developmental functions, a cancer-relevant phenotype.

2024-04-29 | GSE239637 | GEO

Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation [CUT&RUN]

Project description:Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants was exclusively observed on the minor fraction of histone tails harboring the mutations, the same mutants recurrently disrupted broad H3K27me3 domains in the chromatin context, including near developmentally regulated promoters. H3K27me3 loss led to de-repression of differentiation pathways, with concordant effects between H3R2 and H3R26 mutants despite different proximity to the PRC2 substrate, H3K27. Functionally, H3R26C-expressing mesenchymal progenitor cells and murine embryonic stem cell-derived teratomas demonstrated impaired differentiation. Collectively, these data show that cancer-associated H3 N-terminal arginine mutations reduce PRC2 activity and disrupt chromatin-dependent developmental functions, a cancer-relevant phenotype.

2024-04-29 | GSE239636 | GEO

Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation [RNA-Seq]

Project description:Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants was exclusively observed on the minor fraction of histone tails harboring the mutations, the same mutants recurrently disrupted broad H3K27me3 domains in the chromatin context, including near developmentally regulated promoters. H3K27me3 loss led to de-repression of differentiation pathways, with concordant effects between H3R2 and H3R26 mutants despite different proximity to the PRC2 substrate, H3K27. Functionally, H3R26C-expressing mesenchymal progenitor cells and murine embryonic stem cell-derived teratomas demonstrated impaired differentiation. Collectively, these data show that cancer-associated H3 N-terminal arginine mutations reduce PRC2 activity and disrupt chromatin-dependent developmental functions, a cancer-relevant phenotype.

2024-04-29 | GSE239632 | GEO

Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation

Project description:Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation

| PRJNA1000460 | ENA

Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation [scRNA-Seq]

Project description:Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation [scRNA-Seq]

| PRJNA1000469 | ENA

Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation [CUT&RUN]

Project description:Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation [CUT&RUN]

| PRJNA1000464 | ENA

Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation [RNA-Seq]

Project description:Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation [RNA-Seq]

| PRJNA1000463 | ENA

Mutations in Alstrom protein impair terminal differentiation of cardiomyocytes.

Project description:Cardiomyocyte cell division and replication in mammals proceed through embryonic development and abruptly decline soon after birth. The process governing cardiomyocyte cell cycle arrest is poorly understood. Here we carry out whole-exome sequencing in an infant with evidence of persistent postnatal cardiomyocyte replication to determine the genetic risk factors. We identify compound heterozygous ALMS1 mutations in the proband, and confirm their presence in her affected sibling, one copy inherited from each heterozygous parent. Next, we recognize homozygous or compound heterozygous truncating mutations in ALMS1 in four other children with high levels of postnatal cardiomyocyte proliferation. Alms1 mRNA knockdown increases multiple markers of proliferation in cardiomyocytes, the percentage of cardiomyocytes in G2/M phases, and the number of cardiomyocytes by 10% in cultured cells. Homozygous Alms1-mutant mice have increased cardiomyocyte proliferation at 2 weeks postnatal compared with wild-type littermates. We conclude that deficiency of Alström protein impairs postnatal cardiomyocyte cell cycle arrest.

| S-EPMC3992616 | biostudies-literature

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