Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Neurospora crassa

PROVIDER: GSE134445 | GEO | 2022/10/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

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

| PRJNA555141 | ENA

Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration [multiome]

Project description:Germline histone H3.3 amino acid substitutions, including H3.3G34R/V, cause severe neurodevelopmental syndromes. To understand how these mutations impact brain development, we generated H3.3G34R/V/W knock-in mice and identified strikingly distinct developmental defects for each mutation. H3.3G34R-mutants uniquely exhibited progressive microcephaly and neurodegeneration, with abnormal accumulation of disease-associated microglia and concurrent neuronal depletion. G34R severely decreased H3K36me2 on the mutant H3.3 tail, impairing recruitment of DNA methyltransferase DNMT3A. Redistribution of DNMT3A on chromatin promoted sustained expression of complement and other innate immune genes through loss of non-CG (CH) methylation, and silencing of neuronal gene promoters through aberrant CG methylation. Persistent complement expression in G34R neurons led to neuroinflammation possibly accounting for progressive neurodegeneration. Our study reveals that H3.3G34-substitutions have differential impact on the epigenome, which underlie the diverse phenotypes observed, and uncovers unappreciated roles for H3K36me2 and DNMT3A-dependent CH-methylation in modulating synaptic pruning and neuroinflammation in post-natal brains.

2023-03-16 | GSE211387 | GEO

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

Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration [WGBS]

Project description:De novo germline histone H3.3 amino acid substitutions, including H3.3G34R/V, cause severe neurodevelopmental syndromes. To understand how these mutations impact brain development, we generated heterozygous H3.3G34R/V/W direct knock-in mutant mice and identified strikingly distinct developmental defects for each amino acid substitution. H3.3G34R-mutant mice uniquely exhibited progressive microcephaly and neurodegeneration, associated with abnormal accumulation of damage-associated microglia and astrocytes, and concurrent neuronal depletion in postnatal brains. On the mutant H3.3 tail, G34R severely decreased H3K36me2, impairing recruitment of DNA methyltransferase DNMT3A and promoting its redistribution on chromatin. This results in loss of CH methylation at complement and other innate immune genes promoting their sustained expression, and, aberrant CG methylation at neuronal gene promoters and undue silencing. Persistent complement expression in G34R neurons led to excessive synaptic pruning, neuroinflammation, and neuronal damage accounting for progressive neurodegeneration. Our study reveals H3.3G34-substitutions have differential impact on chromatin, which underlie the diverse phenotypes observed. Notably, we uncover unappreciated roles for H3K36me2 and DNMT3A-dependent CH-methylation in modulating pruning and neuroinflammation in post-natal brains.

2023-03-16 | GSE199883 | GEO

Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration [RNA-seq]

2023-03-16 | GSE199882 | GEO

Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration [ChIP-seq]

2023-03-16 | GSE199884 | GEO