Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA552354 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11103327.fastq.gz | Fastqsanger.gz | |||
| SRR11103328.fastq.gz | Fastqsanger.gz | |||
| SRR11103329.fastq.gz | Fastqsanger.gz | |||
| SRR11103330.fastq.gz | Fastqsanger.gz | |||
| SRR11103331.fastq.gz | Fastqsanger.gz |
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Project description:A remarkably high frequency of pediatric gliomas and bone tumors harbor monoallelic, missense mutations in genes encoding histone variant H3.3 at Glycine 34. We find that G34 mutations distinctly impede H3K36 methylation by SETD2. Consequently, the reduction of H3K36 methylation leads to high levels of PRC2-mediated H3K27me3 on G34 mutant nucleosomes. We find that H3.3G34W expression in murine mesenchymal stem cells (mMSCs) promotes aberrant gain of H3K27me2/3 and loss of H3K27ac at active enhancers containing SETD2. mMSCs expressing H3.3G34W display a unique transcriptional program that is dependent on PRC2 activity *in cis* and exhibit enhanced tumor development *in vivo*. Altogether, we demonstrate that H3.3G34 oncohistones selectively promote PRC2 activity by interfering with SETD2-mediated H3K36 methylation. We propose that PRC2-mediated silencing of enhancers involved in cell differentiation represents a potential mechanism that drives these malignancies.
2021-09-23 | GSE133721 | GEO
Project description:A remarkably high frequency of pediatric gliomas and bone tumors harbor monoallelic, missense mutations in genes encoding histone variant H3.3 at Glycine 34. We find that G34 mutations distinctly impede H3K36 methylation by SETD2. Consequently, the reduction of H3K36 methylation leads to high levels of PRC2-mediated H3K27me3 on G34 mutant nucleosomes. We find that H3.3G34W expression in murine mesenchymal stem cells (mMSCs) promotes aberrant gain of H3K27me2/3 and loss of H3K27ac at active enhancers containing SETD2. mMSCs expressing H3.3G34W display a unique transcriptional program that is dependent on PRC2 activity *in cis* and exhibit enhanced tumor development *in vivo*. Altogether, we demonstrate that H3.3G34 oncohistones selectively promote PRC2 activity by interfering with SETD2-mediated H3K36 methylation. We propose that PRC2-mediated silencing of enhancers involved in cell differentiation represents a potential mechanism that drives these malignancies.
2020-10-12 | GSE133718 | GEO
Project description:Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression [ChIP-Seq]
| PRJNA552322 | ENA
Project description:Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression [RNA-Seq]
| PRJNA552324 | ENA
Project description:A high percentage of pediatric gliomas and bone tumors reportedly harbor missense mutations at glycine 34 in genes encoding histone variant H3.3. We find that these H3.3 G34 mutations directly alter the enhancer chromatin landscape of mesenchymal stem cells by impeding methylation at lysine 36 on histone H3 (H3K36) by SETD2, but not by the NSD1/2 enzymes. The reduction of H3K36 methylation by G34 mutations promotes an aberrant gain of PRC2-mediated H3K27me2/3 and loss of H3K27ac at active enhancers containing SETD2 activity. This altered histone modification profile promotes a unique gene expression profile that supports enhanced tumor development in vivo. Our findings are mirrored in G34W-containing giant cell tumors of bone where patient-derived stromal cells exhibit gene expression profiles associated with early osteoblastic differentiation. Overall, we demonstrate that H3.3 G34 oncohistones selectively promote PRC2 activity by interfering with SETD2-mediated H3K36 methylation. We propose that PRC2-mediated silencing of enhancers involved in cell differentiation represents a potential mechanism by which H3.3 G34 mutations drive these tumors.
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Project description:High-throughput sequencing of numerous patient samples has identified a myriad of frequent mutations of epigenetic regulators in human cancers, including recently discovered mutations in histone-encoding genes. Lysine-to-methionine mutations such as H3K27M and H3K36M share a common mechanism of inhibiting methylation pathways at the genome-wide level to promote tumorigenesis. However, the mechanism underlying the molecular and cellular changes due to H3G34 alterations is yet to be determined. H3G34 itself is not post-translationally modified; however, G34 lies in close proximity to K36, which undergoes methylation during transcriptional elongation. In Hela cells, H3.3G34L/W mutations have no effect on global levels of methylation on H3K36, H3K27, or other major methylation sites on endogenous histone H3, which include both H3.3 and the canonical H3.1/H3.2 proteins. However, long exposures of the blots revealed that methylation on the ectopic Flag-H3.3 proteins are affected by G34 mutations: with di- and trimethylation on H3K36 and H3K27ac reduced whereas H3K27me3 increased in the G34L and G34W mutated H3.3 compared to the WT H3.3. ChIP-seq results showed that mutations of H3.3G34 affect methylation on H3K36 and H3K27 in cis. G34L/W mutants abolish SETD2 methylation of H3K36. In contrast, the enzymatic activities of both EZH2 and p300 on H3K27 are not affected by G34 mutations. Consistent with changes in H3K27me3 and H3K36m3 levels, we found increased binding of PRC2 (EZH2, SUZ12 and EED) and PRC1 complex components (CBX8 and RING2) and reduced binding of H3.3K36me3 reader such as ZMYND11 to the G34 mutants. In summary, our study revealed that histone H3.3 G34 mutations alter histone K36 and K27 methylation in cis, and affect the binding of readers specific to K36 or K27 methylation.
2018-04-26 | GSE110389 | GEO
Project description:Pediatric high-grade gliomas (pHGG) are devastating and incurable brain tumors with recurrent mutations in histone H3.3. These mutations promote oncogenesis by dysregulating gene expression through alterations of histone modifications. We identify aberrant DNA repair as an independent mechanism, which fosters genome instability in H3.3 mutant pHGG, and opens new therapeutic options. The two most frequent H3.3 mutations in pHGG, K27M and G34R, drive aberrant repair of replication-associated damage by non-homologous end joining (NHEJ). Aberrant NHEJ is mediated by the DNA repair enzyme Polynucleotide Kinase 3'-Phosphatase (PNKP), which shows increased association with mutant H3.3 at damaged replication forks. PNKP sustains the proliferation of cells bearing H3.3 mutations, thus conferring a molecular vulnerability, specific to mutant cells, with potential for therapeutic targeting.
2024-01-10 | PXD041132 | Pride
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2020-10-12 | GSE133722 | GEO
Project description:Polycomb repressive complex 2 (PRC2) regulates gene expression during lineage specification through trimethylation of lysine 27 on histone H3 (H3K27me3). In Drosophila, polycomb binding sites are dynamic chromatin regions coupled to incorporation of the histone variant H3.3. Here we show in mouse embryonic stem cells (ESCs) that H3.3 is required for proper establishment of H3K27me3 at the promoters of developmentally regulated genes. These promoters show reduced dynamics as determined by deposition of de novo synthesized histones, associated with reduced PRC2 occupancy. H3.3-depleted ESCs show upregulation of extraembryonic trophectoderm, as well as misregulation of other developmental genes upon differentiation. Our data demonstrate the importance of H3.3 incorporation in ESCs and suggest that changes in chromatin dynamics in its absence lead to misregulation of gene expression during differentiation. Moreover, our findings lend support to the emerging notion that H3.3 has multiple functions in distinct genomic locations that are not always correlated with an “active” chromatin state. RNA-seq analysis of three embryonic stem cell lines (control, H3.3 KD1, and H3.3 KD2)
2013-09-30 | E-GEOD-42154 | biostudies-arrayexpress
Project description:Polycomb repressive complex 2 (PRC2) regulates gene expression during lineage specification through trimethylation of lysine 27 on histone H3 (H3K27me3). In Drosophila, polycomb binding sites are dynamic chromatin regions coupled to incorporation of the histone variant H3.3. Here we show in mouse embryonic stem cells (ESCs) that H3.3 is required for proper establishment of H3K27me3 at the promoters of developmentally regulated genes. These promoters show reduced dynamics as determined by deposition of de novo synthesized histones, associated with reduced PRC2 occupancy. H3.3-depleted ESCs show upregulation of extraembryonic trophectoderm, as well as misregulation of other developmental genes upon differentiation. Our data demonstrate the importance of H3.3 incorporation in ESCs and suggest that changes in chromatin dynamics in its absence lead to misregulation of gene expression during differentiation. Moreover, our findings lend support to the emerging notion that H3.3 has multiple functions in distinct genomic locations that are not always correlated with an “active” chromatin state. CATCH-IT analysis of five embryonic stem cell lines (control, H3.3 KD1, and H3.3 KD2; wild type and Hira-/-)
2013-09-30 | E-GEOD-42153 | biostudies-arrayexpress