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The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase

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

ORGANISM(S): Neurospora crassa

PROVIDER: GSE134452 | GEO | 2022/10/19

REPOSITORIES: GEO

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The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase [RNA-seq]

Project description:The recurrent mutation of histone variant H3.3 at glycine-34 (H3.3G34) defines a type of pediatric glioma. Characteristic changes to the epigenome associated with the disease are thought to be the consequence of altered methylation of the adjacent lysine-36 (K36) residue, but the complexity of this regulatory pathway in humans, combined with a multi-component disease etiology, has limited our understanding of how H3.3G34 mutations contribute to oncogenesis. Here we use Neurospora crassa to show that the most common mutation associated with this tumor, glycine to arginine (G34R), drives aberrant heterochromatin formation and abnormal growth by inhibiting the H3K36 methyltransferase ASH1. Inactivation of ASH1, either directly or with H3G34R, drives spurious intergenic DNA methylation, redistribution of H3K27 methylation, and derepression of silent genes. We provide evidence that these defects are largely due to aberrant activity of RNA polymerase II (RNAPII)-associated SET-2, and propose targeted SET-2 inhibition as a therapeutic strategy for H3.3G34R gliomas.

2022-10-19 | GSE134451 | GEO

The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase [ChIP-seq]

2022-10-19 | GSE134449 | GEO

The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase [ATAC-seq]

2022-10-19 | GSE134445 | GEO

The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase

Project description:The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase

| PRJNA555141 | ENA

The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase [ATAC-seq]

Project description:The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase [ATAC-seq]

| PRJNA555417 | ENA

The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase [RNA-seq]

Project description:The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase [RNA-seq]

| PRJNA555433 | ENA

The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase [ChIP-seq]

Project description:The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase [ChIP-seq]

| PRJNA555435 | ENA

Mrg15 stimulates Ash1 H3K36 methyltransferase activity and facilitates Ash1 Trithorax group protein function in Drosophila.

Project description:Ash1 is a Trithorax group protein that possesses H3K36-specific histone methyltransferase activity, which antagonizes Polycomb silencing. Here we report the identification of two Ash1 complex subunits, Mrg15 and Nurf55. In vitro, Mrg15 stimulates the enzymatic activity of Ash1. In vivo, Mrg15 is recruited by Ash1 to their common targets, and Mrg15 reinforces Ash1 chromatin association and facilitates the proper deposition of H3K36me2. To dissect the functional role of Mrg15 in the context of the Ash1 complex, we identify an Ash1 point mutation (Ash1-R1288A) that displays a greatly attenuated interaction with Mrg15. Knock-in flies bearing this mutation display multiple homeotic transformation phenotypes, and these phenotypes are partially rescued by overexpressing the Mrg15-Nurf55 fusion protein, which stabilizes the association of Mrg15 with Ash1. In summary, Mrg15 is a subunit of the Ash1 complex, a stimulator of Ash1 enzymatic activity and a critical regulator of the TrxG protein function of Ash1 in Drosophila.

| S-EPMC5696344 | biostudies-literature

Mrg15 allosterically activates Ash1’s H3K36 methyltransferase activity and facilitates Ash1’s trithorax group protein function in Drosophila

Project description:Ash1 is a classic Trithorax group protein possessing an H3K36-specific histone methyltransferase activity. Ash1 plays a critical role in antagonizing Polycomb silencing and its loss-of-function mutations lead to inactivation of certain Hox genes and homeotic transformation. Here, we report the purification of Ash1 complex with the identification of two novel subunits, Mrg15 and Nurf55. Interestingly, Mrg15 stimulates the enzymatic activity of Ash1 in vitro, and such stimulation is independent of the chromo domain of Mrg15. In vivo, Mrg15 is recruited by Ash1 to their common target genes and Mrg15 is essential for the proper deposition of H3K36me2 at these regions.

2017-10-04 | GSE93100 | GEO

ASH1-catalyzed H3K36 methylation drives gene repression and marks H3K27me2/3-competent chromatin.

Project description:Methylation of histone H3 at lysine 36 (H3K36me), a widely-distributed chromatin mark, largely results from association of the lysine methyltransferase (KMT) SET-2 with RNA polymerase II (RNAPII), but most eukaryotes also have additional H3K36me KMTs that act independently of RNAPII. These include the orthologs of ASH1, which are conserved in animals, plants, and fungi but whose function and control are poorly understood. We found that Neurospora crassa has just two H3K36 KMTs, ASH1 and SET-2, and were able to explore the function and distribution of each enzyme independently. While H3K36me deposited by SET-2 marks active genes, inactive genes are modified by ASH1 and its activity is critical for their repression. ASH1-marked chromatin can be further modified by methylation of H3K27, and ASH1 catalytic activity modulates the accumulation of H3K27me2/3 both positively and negatively. These findings provide new insight into ASH1 function, H3K27me2/3 establishment, and repression in facultative heterochromatin.

| S-EPMC6251624 | biostudies-literature

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