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Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional disruptions

ABSTRACT: Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional disruptions

PROVIDER: PRJNA935357 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23490049_1.fastq.gz	Fastqsanger.gz
	SRR23490049_2.fastq.gz	Fastqsanger.gz
	SRR23490050_1.fastq.gz	Fastqsanger.gz
	SRR23490050_2.fastq.gz	Fastqsanger.gz
	SRR23490051_1.fastq.gz	Fastqsanger.gz

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Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional disruptions

Project description:Phenotypic heterogeneity in monogenic neurodevelopmental disorders can arise from differential severity of variants underlying disease, but how distinct alleles drive variable disease presentation is not well understood. Here, we investigate missense mutations in DNMT3A, a DNA methyltransferase associated with overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity. We generate a DNMT3A P900L/+ mouse mimicking a mutation with mild-to-moderate severity, and compare phenotypic and epigenomic effects with a severe R878H mutation. P900L mutants exhibit core growth and behavioral phenotypes shared across models but show subtle epigenomic changes, while R878H mutants display extensive disruptions. We identify mutation-specific dysregulated genes which may contribute to variable disease severity. Shared transcriptomic disruption identified across mutations overlaps dysregulation observed in other developmental disorder models and likely drives common phenotypes. Together, our findings define central drivers of DNMT3A disorders and illustrate how variable epigenomic disruption contributes to phenotypic heterogeneity in neurodevelopmental disease.

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Transcriptomic and epigenetic disruptions in excitatory neurons in Dnmt3a conditional knockout mouse

Project description:We created a mouse line in which deletion of exon 19 of Dnmt3a is driven by the Neurod6 promoter (also known as Nex-Cre line). In this conditional knockout (cKO), Dnmt3a is functionally ablated in excitatory neurons in the neocortex and hippocampus starting in mid/late gestation (~E13-15). With an affinity purification approach to isolate tagged nuclei in mice (similar to INTACT; [Deal R.B. and Henikoff S. A simple method for gene expression and chromatin profiling of individual cell types within a tissue. Dev. Cell 18,1030-1040. (2010)]), we characterized the genome-wide patterns of transcription, DNA methylation, and histone modifications in excitatory pyramidal neurons of the frontal cortex from the Dnmt3a cKO and control mice. Our data provide a detailed assessment of the molecular basis of the accompanying changes of neurophysiological and behavioral phenotypes in the cKO mice, and suggest a complex interaction between DNA methylation and Polycomb-mediated repression in the epigenetic regulation in developing brain cells.

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Transcriptomic and epigenetic disruptions in excitatory neurons in Dnmt3a conditional knockout mouse

Project description:Transcriptomic and epigenetic disruptions in excitatory neurons in Dnmt3a conditional knockout mouse

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Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional deficits.

Project description: Not available

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Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional deficits.

Project description: Not available

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DNMT3A haploinsufficiency results in behavioral deficits and global epigenomic dysregulation shared across neurodevelopment disorders [Bisulfite-Seq]

Project description:Mutations in DNA methyltransferase 3A (DNMT3A) have been detected in autism and related disorders, but how these mutations disrupt nervous system function is unknown. Here we define the effects of neurodevelopmental disease-associated DNMT3A mutations. We show that diverse mutations affect different aspects of protein activity yet lead to shared deficiencies in neuronal DNA methylation. Heterozygous DNMT3A knockout mice mimicking DNMT3A disruption in disease display growth and behavioral alterations consistent with human phenotypes. Strikingly, in these mice we detect global disruption of neuron-enriched non-CG DNA methylation, a binding site for the Rett syndrome protein MeCP2. Loss of this methylation leads to enhancer and gene dysregulation that overlaps with models of Rett syndrome and autism. These findings define effects of DNMT3A haploinsufficiency in the brain and uncover disruption of the non-CG methylation pathway as a convergence point across neurodevelopmental disorders.

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DNMT3A haploinsufficiency results in behavioral deficits and global epigenomic dysregulation shared across neurodevelopment disorders [ChIP-seq]

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DNMT3A haploinsufficiency results in behavioral deficits and global epigenomic dysregulation shared across neurodevelopment disorders [RNA-Seq]

2020-11-13 | GSE147818 | GEO

Gut Microbiota from Human Autism Spectrum Disorder Induces Behavioral Deficits in Mice

Project description:Gut Microbiota from Human Autism Spectrum Disorder Induces Behavioral Deficits in Mice

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DNMT3A haploinsufficiency results in behavioral deficits and global epigenomic dysregulation shared across neurodevelopment disorders

Project description:DNMT3A haploinsufficiency results in behavioral deficits and global epigenomic dysregulation shared across neurodevelopment disorders

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