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

ABSTRACT: Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration

PROVIDER: PRJNA821884 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18560414_1.fastq.gz	Fastqsanger.gz
	SRR18560414_2.fastq.gz	Fastqsanger.gz
	SRR18560415_1.fastq.gz	Fastqsanger.gz
	SRR18560415_2.fastq.gz	Fastqsanger.gz
	SRR18560416_1.fastq.gz	Fastqsanger.gz

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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 [ChIP-seq]

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

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

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

| PRJNA870081 | ENA

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

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

| PRJNA821890 | 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.

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

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

| PRJNA821891 | ENA

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

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

| PRJNA821892 | ENA

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-03-16 | GSE199885 | GEO

Aggregation of α-synuclein scaffolds RNA G-quadruplexes assembly leading to progressive neurodegeneration

Project description:Synucleinopathies are triggered by the aggregation of α-synuclein (αSyn), leading to progressive neurodegeneration. However, the intracellular mechanism of αSyn aggregation remains unclear. Here we show that assembly of RNA G-quadruplexes (rG4s) form scaffolds for αSyn aggregation, contributing to neurodegeneration. Purified αSyn binds rG4s directly through the N-terminus. rG4 itself undergoes phase separation and assembly by Ca2+, accelerating the sol-gel phase transition of αSyn. In αSyn preformed fibrils (PFF)-treated neurons, rG4s assembly composed of synaptic mRNAs co-aggregates with αSyn upon Ca2+ excess influx into cytoplasm, eliciting synaptic dysfunction. Artificial assembly of rG4s using an optogenetic approach evokes αSyn aggregation and neuronal dysfunction. Administration of 5-aminolevulinic acid (5-ALA), a prodrug of protoporphyrin IX (PpIX) that prevents phase separation of rG4s, attenuating αSyn aggregation, neurodegeneration, and progressive motor deficits in PFF-injected synucleinopathy mice. Together, assembly of rG4s due to dysregulation of intracellular Ca2+ homeostasis accelerates αSyn phase transition and aggregation may contribute to pathogenesis of synucleinopathies.

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