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

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

ORGANISM(S): Mus musculus

PROVIDER: GSE147899 | GEO | 2020/11/13

REPOSITORIES: GEO

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DNMT3A Haploinsufficiency Results in Behavioral Deficits and Global Epigenomic Dysregulation Shared across Neurodevelopmental Disorders.

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 DNMT3A mutations associated with neurodevelopmental disease. We show that diverse mutations affect different aspects of protein activity but 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 the effects of DNMT3A haploinsufficiency in the brain and uncover disruption of the non-CG methylation pathway as a convergence point across neurodevelopmental disorders.

| S-EPMC7716597 | biostudies-literature

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.

2020-11-13 | GSE147898 | GEO

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

2020-11-13 | GSE147818 | GEO

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

2020-11-13 | GSE147867 | GEO

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

| PRJNA622496 | ENA

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

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

| PRJNA622502 | ENA

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

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

| PRJNA621177 | ENA

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

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

| PRJNA622433 | ENA

Behavioral training rescues motor deficits in Cyfip1 haploinsufficiency mouse model of autism spectrum disorders.

Project description:Deletions in the 15q11.2 region of the human genome are associated with neurobehavioral deficits, and motor development delay, as well as in some cases, symptoms of autism or schizophrenia. The cytoplasmic FMRP-interacting protein 1 (CYFIP1) is one of the four genes contained within this locus and has been associated with other genetic forms of autism spectrum disorders (ASD). In mice, Cyfip1 haploinsufficiency leads to alteration of dendritic spine morphology and defects in synaptic plasticity, two pathophysiological hallmarks of mouse models of ASD. At the behavioral level, however, Cyfip1 haploinsufficiency leads to minor phenotypes, not directly relevant for 15q11.2 deletion syndrome or ASD. A fundamental question is whether neuronal phenotypes caused by the mutation of Cyfip1 are relevant for the human condition. Here, we describe a synaptic cluster of ASD-associated proteins centered on CYFIP1 and the adhesion protein Neuroligin-3. Cyfip1 haploinsufficiency in mice led to decreased dendritic spine density and stability associated with social behavior and motor learning phenotypes. Behavioral training early in development resulted in alleviating the motor learning deficits caused by Cyfip1 haploinsufficiency. Altogether, these data provide new insight into the neuronal and behavioral phenotypes caused by Cyfip1 mutation and proof-of-concept for the development of a behavioral therapy to treat phenotypes associated with 15q11.2 syndromes and ASD.

| S-EPMC6341103 | biostudies-literature

Neuregulin-2 ablation results in dopamine dysregulation and severe behavioral phenotypes relevant to psychiatric disorders.

Project description:Numerous genetic and functional studies implicate variants of Neuregulin-1 (NRG1) and its neuronal receptor ErbB4 in schizophrenia and many of its endophenotypes. Although the neurophysiological and behavioral phenotypes of NRG1 mutant mice have been investigated extensively, practically nothing is known about the function of NRG2, the closest NRG1 homolog. We found that NRG2 expression in the adult rodent brain does not overlap with NRG1 and is more extensive than originally reported, including expression in the striatum and medial prefrontal cortex (mPFC), and therefore generated NRG2 knockout mice (KO) to study its function. NRG2 KOs have higher extracellular dopamine levels in the dorsal striatum but lower levels in the mPFC; a pattern with similarities to dopamine dysbalance in schizophrenia. Like ErbB4 KO mice, NRG2 KOs performed abnormally in a battery of behavioral tasks relevant to psychiatric disorders. NRG2 KOs exhibit hyperactivity in a novelty-induced open field, deficits in prepulse inhibition, hypersensitivity to amphetamine, antisocial behaviors, reduced anxiety-like behavior in the elevated plus maze and deficits in the T-maze alteration reward test-a task dependent on hippocampal and mPFC function. Acute administration of clozapine rapidly increased extracellular dopamine levels in the mPFC and improved alternation T-maze performance. Similar to mice treated chronically with N-methyl-d-aspartate receptor (NMDAR) antagonists, we demonstrate that NMDAR synaptic currents in NRG2 KOs are augmented at hippocampal glutamatergic synapses and are more sensitive to ifenprodil, indicating an increased contribution of GluN2B-containing NMDARs. Our findings reveal a novel role for NRG2 in the modulation of behaviors with relevance to psychiatric disorders.

| S-EPMC5608621 | biostudies-literature

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