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

Christian, Diana L.; Wu, Dennis Y.; Martin, Jenna R.; Moore, J. Russell; Liu, Yiran R.; Clemens, Adam; Nettles, Sabin A.; Kirkland, Nicole M.; Papouin, Thomas; Hill, Cheryl A.; Wozniak, David F.; Dougherty, Joseph D.; Gabel, Harrison W.

doi:10.1016/j.celrep.2020.108416

Cited by 45 publications

(97 citation statements)

References 100 publications

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“…SCZ-like symptoms (including auditory hallucinations) were also recently reported in three patients with novel, predicted deleterious variants in the DNMT3A-coding sequence [255]. Mice hemizygous for Dnmt3a also exhibit behavioral deficits, including reduced exploration and increased anxiety-like behaviors [256]. However, no deficits in pre-pulse inhibition (PPI), a common deficit in patients with SCZ, were observed in these mice.…”

Section: Shared Roles Of Mir-29 and Mir-132-3p: Cortical Ocular Dominance Plasticity And Dnmt3amentioning

confidence: 81%

MicroRNAs in the Onset of Schizophrenia

Thomas

Zakharenko

2021

Cells

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Mounting evidence implicates microRNAs (miRNAs) in the pathology of schizophrenia. These small noncoding RNAs bind to mRNAs containing complementary sequences and promote their degradation and/or inhibit protein synthesis. A single miRNA may have hundreds of targets, and miRNA targets are overrepresented among schizophrenia-risk genes. Although schizophrenia is a neurodevelopmental disorder, symptoms usually do not appear until adolescence, and most patients do not receive a schizophrenia diagnosis until late adolescence or early adulthood. However, few studies have examined miRNAs during this critical period. First, we examine evidence that the miRNA pathway is dynamic throughout adolescence and adulthood and that miRNAs regulate processes critical to late neurodevelopment that are aberrant in patients with schizophrenia. Next, we examine evidence implicating miRNAs in the conversion to psychosis, including a schizophrenia-associated single nucleotide polymorphism in MIR137HG that is among the strongest known predictors of age of onset in patients with schizophrenia. Finally, we examine how hemizygosity for DGCR8, which encodes an obligate component of the complex that synthesizes miRNA precursors, may contribute to the onset of psychosis in patients with 22q11.2 microdeletions and how animal models of this disorder can help us understand the many roles of miRNAs in the onset of schizophrenia.

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Section: Shared Roles Of Mir-29 and Mir-132-3p: Cortical Ocular Dominance Plasticity And Dnmt3amentioning

confidence: 81%

MicroRNAs in the Onset of Schizophrenia

Thomas

Zakharenko

2021

Cells

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“…The lack of differential expression levels of Pgc1α as a function of brain region was further confirmed by RT-PCR in an independent cohort of males, in which we probed the levels of the reference gene and the SSR-SINE-exon 2 isoform (Fig S4C). Analysis of publicly available RNA-seq data from male and female brain (Christian et al, 2020) showed that levels of the reference or SSR-SINE-exon 2 isoforms were not different based on sex (Fig S4D). Thus, the loss of the protein derived from the SSR-SINE-exon 2 isoform leads to a sexually dimorphic cerebellar transcriptional profile that cannot to be simply explained by differences in its expression in male or female brains.…”

Section: Sine-mutant Female Mice Exhibit Increased Neurotransmitterassociated Gene Expression In the Cerebellummentioning

confidence: 99%

A brain-specific pgc1α fusion transcript affects gene expression and behavioural outcomes in mice

Lozoya

Grenet

et al. 2021

Life Sci. Alliance

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PGC1α is a transcriptional coactivator in peripheral tissues, but its function in the brain remains poorly understood. Various brain-specific Pgc1α isoforms have been reported in mice and humans, including two fusion transcripts (FTs) with non-coding repetitive sequences, but their function is unknown. The FTs initiate at a simple sequence repeat locus ∼570 Kb upstream from the reference promoter; one also includes a portion of a short interspersed nuclear element (SINE). Using publicly available genomics data, here we show that the SINE FT is the predominant form of Pgc1α in neurons. Furthermore, mutation of the SINE in mice leads to altered behavioural phenotypes and significant up-regulation of genes in the female, but not male, cerebellum. Surprisingly, these genes are largely involved in neurotransmission, having poor association with the classical mitochondrial or antioxidant programs. These data expand our knowledge on the role of Pgc1α in neuronal physiology and suggest that different isoforms may have distinct functions. They also highlight the need for further studies before modulating levels of Pgc1α in the brain for therapeutic purposes.

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“…In mature neurons, DNMTs expression was maintained at a high level, and DNMT3A knockout induced the synaptic alteration and learning de cit, which directly in uenced learning and memory behavior, thus DNMT3A in the postmitotic neuron was a key regulator in memory formation [71]. DNMT3A loss caused widespread transcriptional alterations and severe impairment of neuronal function [72], and DNMT3A Haploinsu ciency in the brain led to neurodevelopmental disorders involved in growth and behavioral alterations [73]. Recently, it has been revealed that hypoxic preconditioning exerted anti-hypoxic neuroprotection and maintained HT22 cell proliferation and viability through downregulation of the expression levels of DNMT3A and DNMT3B mRNA and protein [74].…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine Reduces Propofol-Induced Hippocampal Neuron Injury by Modulating the miR-377-5p/Arc Pathway

Zong

Ding

Zeng

et al. 2021

Preprint

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BackgroundPropofol and dexmedetomidine (DEX) are widely used in general anesthesia, and exert toxic and protective effects on hippocampal neurons, respectively. The study sought to investigate the molecular mechanisms of DEX-mediated neuroprotection against propofol-induced hippocampal neuron injury in mouse brains.MethodsHippocampal neurons of mice were treated with propofol, DEX, and propofol+DEX in vitro and in vivo. Neuronal apoptosis was evaluated by a means of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) or Hochest 33258 staining; Arc positive expression in hippocampus tissues was detected using a microscope in immunohistochemistry assays; miRNA-377-5p expression levels were quantified by RT-PCR; the protein levels of Arc, DNMT3A, and DNMT3B were determined using western blot; CCK-8 kit was used to evaluated neuron viability; methylation analysis in miR-377-5p promoter was performed through the methylated DNA immunoprecipitation (MeDIP) assay; luciferase reporter assay was performed to confirm whether Arc was under targeted regulation of miR-377-5p.Results In the current study, both in vitro and in vivo, propofol treatment induced hippocampal neuron apoptosis and suppressed cell viability. DNMT3A and DNMT3B expression levels were decreased following propofol treatment, resulting in lowered methylation in the miR-377-5p promoter region and then enhanced expression of miR-377-5p, leading to a decrease in the expression level of downstream Arc. Conversely, the expression levels of DNMT3A and DNMT3B were increased following DEX treatment, thus methylation in miR-377-5p promoter region was improved, and miR-377-5p expression levels were decreased, leading to an increase in the expression level of downstream Arc. Finally, DEX pretreatment protected hippocampal neurons against propofol-induced neurotoxicity by recover the expression levels of DNMT3A, miR-377-5p, and Arc to the normal levels.ConclusionsDEX reduced propofol-induced hippocampal neuron injury via the miR-377-5p/Arc signaling pathway.

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

Cited by 45 publications

References 100 publications

MicroRNAs in the Onset of Schizophrenia

MicroRNAs in the Onset of Schizophrenia

A brain-specific pgc1α fusion transcript affects gene expression and behavioural outcomes in mice

Dexmedetomidine Reduces Propofol-Induced Hippocampal Neuron Injury by Modulating the miR-377-5p/Arc Pathway

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