Hutnick LK, Golshani P, Namihira M, Xue Z, Matynia A, Yang XW et al. DNA hypomethylation restricted to the murine forebrain induces cortical degeneration and impairs postnatal neuronal maturation. Hum Mol Genet 18: 2875

Department of Human Genetics, David Geffen School of Medicine, University of California at Los Angeles, 695 Charles Young Drive South, Los Angeles, CA 90095, USA.
Human Molecular Genetics (Impact Factor: 6.39). 06/2009; 18(15):2875-88. DOI: 10.1093/hmg/ddp222
Source: PubMed


DNA methylation is a major epigenetic factor regulating genome reprogramming, cell differentiation and developmental gene expression. To understand the role of DNA methylation in central nervous system (CNS) neurons, we generated conditional Dnmt1 mutant mice that possess approximately 90% hypomethylated cortical and hippocampal cells in the dorsal forebrain from E13.5 on. The mutant mice were viable with a normal lifespan, but displayed severe neuronal cell death between E14.5 and three weeks postnatally. Accompanied with the striking cortical and hippocampal degeneration, adult mutant mice exhibited neurobehavioral defects in learning and memory in adulthood. Unexpectedly, a fraction of Dnmt1(-/-) cortical neurons survived throughout postnatal development, so that the residual cortex in mutant mice contained 20-30% of hypomethylated neurons across the lifespan. Hypomethylated excitatory neurons exhibited multiple defects in postnatal maturation including abnormal dendritic arborization and impaired neuronal excitability. The mutant phenotypes are coupled with deregulation of those genes involved in neuronal layer-specification, cell death and the function of ion channels. Our results suggest that DNA methylation, through its role in modulating neuronal gene expression, plays multiple roles in regulating cell survival and neuronal maturation in the CNS.

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Available from: Felix Schweizer, Sep 22, 2014
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    • "To examine the role of DNA methyltransferases in adult brain, mice lacking Dnmt1 and Dnmt3a have been generated. Constitutive Dnmt1 and Dnmt3a knockout mice are not viable, thus research on the role of DNMTs in adult brain function has utilized conditional knockout mice (Fan et al., 2001; Feng et al., 2010; Golshani, Hutnick, Schweizer, & Fan, 2005; Hutnick et al., 2009; LaPlant et al., 2010; Li, Bestor, & Jaenisch, 1992; Nguyen, Meletis, Fu, Jhaveri, & Jaenisch, 2007; Okano, Bell, Haber, & Li, 1999). In the current study we investigated the impact of a postnatal, forebrain-specific conditional knockout (CKO) of Dnmt1 or Dnmt3a on 1074-7427/Ó 2014 Elsevier Inc. "
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    ABSTRACT: Methylation of cytosine nucleotides is governed by DNA methyltransferases (DNMTs) that establish de novo DNA methylation patterns in early embryonic development (e.g., DNMT3a and DNMT3b) or maintain those patterns on hemimethylated DNA in dividing cells (e.g., DNMT1). DNMTs continue to be expressed at high levels in mature neurons, however their impact on neuronal function and behavior are unclear. To address this issue we examined DNMT1 and DNMT3a expression following associative learning. We also generated forebrain specific conditional Dnmt1 or Dnmt3a knockout mice and characterized them in learning and memory paradigms as well as for alterations in long-term potentiation (LTP) and synaptic plasticity. Here, we report that experience in an associative learning task impacts expression of Dnmt3a, but not Dnmt1, in brain areas that mediate learning of this task. We also found that Dnmt3a knockout mice, and not Dnmt1 knockouts have synaptic alterations as well as learning deficits on several associative and episodic memory tasks. These findings indicate that the de novo DNA methylating enzyme DNMT3a in postmitotic neurons is necessary for normal memory formation and its function cannot be substituted by the maintenance DNA methylating enzyme DNMT1.
    Neurobiology of Learning and Memory 06/2014; 115. DOI:10.1016/j.nlm.2014.06.005 · 3.65 Impact Factor
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    • "The maintenance and differentiation of neural progenitors in these two regions are regulated by many molecular players and signaling pathways, including niche signals, neurotransmitters, growth factors, transcriptional factors, and epigenetic regulators (Mu et al., 2010; Zhao et al., 2008). DNA methylation at cytosines (5-methylcytosine [5mC]) plays an important role in adult neurogenesis by regulating the proliferation and survival of neural progenitors as well as dendritic growth of newborn neurons in both embryonic and adult brains (Fan et al., 2005; Hutnick et al., 2009; Ma et al., 2009; Wu et al., 2010). A new form of DNA modification, 5-hydroxymethylcytosine (5hmC), was discovered recently in mammalian pluripotent stem cells and brains (Kriaucionis and Heintz, 2009). "
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    ABSTRACT: DNA hydroxylation catalyzed by Tet dioxygenases occurs abundantly in embryonic stem cells and neurons in mammals. However, its biological function in vivo is largely unknown. Here, we demonstrate that Tet1 plays an important role in regulating neural progenitor cell proliferation in adult mouse brain. Mice lacking Tet1 exhibit impaired hippocampal neurogenesis accompanied by poor learning and memory. In adult neural progenitor cells deficient in Tet1, a cohort of genes involved in progenitor proliferation were hypermethylated and downregulated. Our results indicate that Tet1 is positively involved in the epigenetic regulation of neural progenitor cell proliferation in the adult brain.
    Cell stem cell 06/2013; 13(2). DOI:10.1016/j.stem.2013.05.006 · 22.27 Impact Factor
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    • "While loss of genomic DNA methylation contributes to locus- and gene-specific changes in DNA methylation, it also leads to broader effects such as chromosomal instability, aberrant activation of endogenous retroviral elements, and loss of imprinting [42] Little is known about the effects of global DNA hypomethylation in the CNS, however, forebrain-specific DNA methyltransferase 1 (DNMT1) knockout animals (which demonstrate global hypomethylation) provide some information. These animals have progressive neurodegeneration, altered neuronal gene expression, and severe degeneration of cortical neurons [43], [44]. Additionally, global DNA hypomethylation has been associated with neural tube defect affected pregnancies [45]. "
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    ABSTRACT: Maternal consumption of a high fat diet during pregnancy increases the offspring risk for obesity. Using a mouse model, we have previously shown that maternal consumption of a high fat (60%) diet leads to global and gene specific decreases in DNA methylation in the brain of the offspring. The present experiments were designed to attempt to reverse this DNA hypomethylation through supplementation of the maternal diet with methyl donors, and to determine whether methyl donor supplementation could block or attenuate phenotypes associated with maternal consumption of a HF diet. Metabolic and behavioral (fat preference) outcomes were assessed in male and female adult offspring. Expression of the mu-opioid receptor and dopamine transporter mRNA, as well as global DNA methylation were measured in the brain. Supplementation of the maternal diet with methyl donors attenuated the development of some of the adverse effects seen in offspring from dams fed a high fat diet; including weight gain, increased fat preference (males), changes in CNS gene expression and global hypomethylation in the prefrontal cortex. Notable sex differences were observed. These findings identify the importance of balanced methylation status during pregnancy, particularly in the context of a maternal high fat diet, for optimal offspring outcome.
    PLoS ONE 05/2013; 8(5):e63549. DOI:10.1371/journal.pone.0063549 · 3.23 Impact Factor
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