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Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [NeuN+ hippocampal neurons]

ABSTRACT: Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [NeuN+ hippocampal neurons]

PROVIDER: PRJNA998839 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25434000_1.fastq.gz	Fastqsanger.gz
	SRR25434000_2.fastq.gz	Fastqsanger.gz
	SRR25434001_1.fastq.gz	Fastqsanger.gz
	SRR25434001_2.fastq.gz	Fastqsanger.gz
	SRR25434002_1.fastq.gz	Fastqsanger.gz

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Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [NeuN+ hippocampal neurons]

Project description:Many Mendelian developmental disorders caused by coding variants in epigenetic regulators have now been discovered. Epigenetic regulators are broadly expressed, and each of these disorders typically exhibits phenotypic manifestations from many different organ systems. An open question is whether the chromatin disruption -- the root of the pathogenesis -- is similar in the different disease-relevant cell types. This is possible in principle, since all these cell-types are subject to effects from the same causative gene, that has the same kind of function (e.g. methylates histones) and is disrupted by the same germline variant. We focus on mouse models for Kabuki syndrome types 1 and 2, and find that the chromatin accessibility abnormalities in neurons are mostly distinct from those in B or T cells. This is not because the neuronal abnormalities occur at regulatory elements that are only active in neurons. Neurons, but not B or T cells, show preferential chromatin disruption at CpG islands and at regulatory elements linked to aging. A sensitive analysis reveals that the regions disrupted in B/T cells do exhibit chromatin accessibility changes in neurons, but these are very subtle and of uncertain functional significance. Finally, we identify a small set of regulatory elements disrupted in all three cell types. Our findings reveal the cellular-context-specific effect of variants in epigenetic regulators, and suggest that blood-derived episignatures may not be well-suited for understanding the mechanistic basis of neurodevelopment in Mendelian disorders of the epigenetic machinery.

2023-07-31 | GSE239338 | GEO

Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [NeuN+ hippocampal neurons]

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Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [NeuN+ hippocampal neurons]

Project description:Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [NeuN+ hippocampal neurons]

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Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [CD90.2+ T cells]

2023-07-31 | GSE239337 | GEO

Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice

Project description:Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice

| PRJNA998832 | ENA

Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [CD90.2+ T cells, RNA-seq]

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Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [CD90.2+ T cells]

Project description:Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [CD90.2+ T cells]

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Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [CD90.2+ T cells, RNA-seq]

Project description:Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [CD90.2+ T cells, RNA-seq]

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Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice

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

2023-07-31 | GSE239339 | GEO

A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome

Project description:Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus, and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/βGeo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/βGeo mice modulates H3ac and H3K4me3 in the granular cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/βGeo mice; similar effects on neurogenesis were observed upon exogenous administration of beta-hydroxybutyrate. These data suggests that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders. We used microarrays to query global gene expression changes in the hippocampus of wild type and Kmt2d+/βGeo (Kabuki syndrome model) mice on a regular diet to identify specific gene expression abnormalities in the hippocampus of the Kabuki syndrome mouse model.

2016-12-03 | GSE90836 | GEO