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Histone H3.3 G34 mutations alter histone H3K36 and H3K27 methylation in cis

ABSTRACT: Histone H3.3 G34 mutations alter histone H3K36 and H3K27 methylation in cis

PROVIDER: PRJNA433584 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6701640.fastq.gz	Fastqsanger.gz
	SRR6701650.fastq.gz	Fastqsanger.gz
	SRR6701641.fastq.gz	Fastqsanger.gz
	SRR6701651.fastq.gz	Fastqsanger.gz
	SRR6701642.fastq.gz	Fastqsanger.gz

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Histone H3.3 G34 mutations alter histone H3K36 and H3K27 methylation in cis

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

Histone H3.3 G34 Mutations Alter Histone H3K36 and H3K27 Methylation In Cis.

Project description:Histone H3 encoding genes, particularly H3F3A and H3F3B, the genes encoding the variant histone H3.3, are mutated at high frequency in pediatric brain and bone malignancies. Compared to the extensive studies on K27M and K36M mutations, little is known about the mechanism of G34 mutations found in pediatric glioblastoma or giant cell tumors of the bone. Here we report that unlike the K27M or K36M that affect global histone methylation, the giant cell tumors of the bone G34 mutations (G34L/W) only affect histone H3K36 and H3K27 methylation on the same mutated histone tails (in cis), a mechanism distinct from known histone mutations.

| S-EPMC6450091 | biostudies-literature

Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression [ChIP-Seq]

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

Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression [RNA-Seq]

2021-09-23 | GSE133721 | GEO

Coordinated Maintenance of H3K36/K27 Methylation by Histone Demethylases Preserves Germ Cell Identity and Immortality

Project description:Germ cells have evolved unique mechanisms to ensure an everlasting transmission of their genetic and epigenetic information to future generations, whose alteration compromises germ cell immortality. In many instances, epigenetic factors play fundamental roles in these mechanisms. Despite H3K36 and H3K27 methyltransferases shape and propagate over generations a pattern of histone methylation essential for C. elegans germ cell maintenance, the role of respective histone demethylases in this context remains mainly unexplored. Here, we show that jmjd-5 regulates the level of H3K36me2 and H3K27me3, preserves germ cell immortality at high temperature and protects germ cell identity by controlling somatic and germline gene expression. Strikingly, the biological and transcriptional effects of jmjd-5 loss can be hindered by the removal of demethylases for H3K27, indicating that H3K36/K27 demethylases act in a transcriptional framework and promote the accurate balance between H3K36 and H3K27 methylation required for the maintenance of germ cell immortality. Furthermore, we found that in wild-type, but not in jmjd-5 mutant animals, alterations of H3K27 and H3K36 methylation and transcription occur at high temperature, suggesting a role for jmjd-5 in adaptation to environmental changes.

2021-11-23 | GSE174652 | GEO

Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression

Project description:Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression

| PRJNA552354 | ENA

H3K36 mutations promote sarcomagenesis through genome-wide remodeling of H3K36 and H3K27 methylation

Project description:H3K36 mutations promote sarcomagenesis through genome-wide remodeling of H3K36 and H3K27 methylation

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Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression.

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.

| S-EPMC7959516 | biostudies-literature

H3K36 mutations promote sarcomagenesis through genome-wide remodeling of H3K36 and H3K27 methylation [H31_ChIP-Rx]

Project description:H3K36 mutations promote sarcomagenesis through genome-wide remodeling of H3K36 and H3K27 methylation [H31_ChIP-Rx]

| PRJNA305536 | ENA

Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression [ChIP-Seq]

Project description:Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression [ChIP-Seq]

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