Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons.
ABSTRACT Dnmt1 and Dnmt3a are important DNA methyltransferases that are expressed in postmitotic neurons, but their function in the CNS is unclear. We generated conditional mutant mice that lack Dnmt1, Dnmt3a or both exclusively in forebrain excitatory neurons and found that only double knockout (DKO) mice showed abnormal long-term plasticity in the hippocampal CA1 region together with deficits in learning and memory. Although we found no neuronal loss, hippocampal neurons in DKO mice were smaller than in the wild type; furthermore, DKO neurons showed deregulated expression of genes, including the class I MHC genes and Stat1, that are known to contribute to synaptic plasticity. In addition, we observed a significant decrease in DNA methylation in DKO neurons. We conclude that Dnmt1 and Dnmt3a are required for synaptic plasticity, learning and memory through their overlapping roles in maintaining DNA methylation and modulating neuronal gene expression in adult CNS neurons.
Full-textDOI: · Available from: Yu Zhou, Sep 19, 2014
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ABSTRACT: Chronic pain arising from peripheral inflammation and tissue or nerve injury is a common clinical symptom. Although intensive research on the neurobiological mechanisms of chronic pain has been carried out during previous decades, this disorder is still poorly managed by current drugs such as opioids and nonsteroidal anti-inflammatory drugs. Inflammation, tissue injury and/or nerve injury-induced changes in gene expression in sensory neurons of the dorsal root ganglion, spinal cord dorsal horn and pain-associated brain regions are thought to participate in chronic pain genesis; however, how these changes occur is still elusive. Epigenetic modifications including DNA methylation and covalent histone modifications control gene expression. Recent studies have shown that peripheral noxious stimulation changes DNA methylation and histone modifications and that these changes may be related to the induction of pain hypersensitivity under chronic pain conditions. This review summarizes the current knowledge and progress in epigenetic research in chronic pain and discusses the potential role of epigenetic modifications as therapeutic antinociceptive targets in this disorder.Epigenomics 04/2015; 7(2):235-245. DOI:10.2217/epi.14.75 · 5.22 Impact Factor
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ABSTRACT: The establishment of synaptic plasticity and long-term memory requires lasting cellular and molecular modifications that, as a whole, must endure despite the rapid turnover of their constituent parts. Such a molecular feat must be mediated by a stable, self-perpetuating, cellular information storage mechanism. DNA methylation, being the archetypal cellular information storage mechanism, has been heavily implicated as being necessary for stable activity-dependent transcriptional alterations within the CNS. This review details the foundational discoveries from both gene-targeted and whole-genome sequencing studies that have brought DNA methylation to our attention as a chief regulator of activity- and experience-dependent transcriptional alterations within the CNS. We present a hypothetical framework to resolve disparate experimental findings regarding distinct manipulations of DNA methylation and their effect on memory, taking into account the unique impact activity-dependent alterations in DNA methylation potentially have on both memory-promoting and memory-suppressing gene expression. And last, we discuss potential avenues for future inquiry into the role of DNA methylation during remote memory formation. © The Author(s) 2015.The Neuroscientist 04/2015; DOI:10.1177/1073858415579635 · 7.62 Impact Factor
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ABSTRACT: The 5-hydroxymethylcytosine (5-hmC) is known to exist as a predictive indicator for a variety of cancers, neurological abnormalities and other perilous diseases. The precursor of 5-hmC i.e. 5-methylcytosine (5mC) has already gained attention as an important epigenetic regulator whereas 5-hmC remains less explored. The two modified DNA bases (5mC and 5-hmC) have absolute diverse distribution, i.e. 5-hmC is mostly restrained to the 5' end of DNA with levels directing the gene transcription whereas 5mC is mainly located at the intra- or intergenic regions of DNA repeats and within certain gene bodies. It has been reported that levels of 5-hmC in different tissues provide a useful tool for detecting numerous associated diseases and their progression. Therefore, to unravel the role of hydroxymethylation in various resulting diseases in humans, comprehensive information on this crucial process has been explored and compiled for its implication in DNA repair system. The role of miRNAs in cancer through hypo- and hypermethylation has also been explored and discussed. In this review, a broad and exclusive insight into hydroxymethylation and its association with repair mechanisms is extensively presented and it is estimated that the accessible information will be of utmost use to the biological community working in the relevant research area. Copyright © 2015. Published by Elsevier B.V.Gene 04/2015; 564(2). DOI:10.1016/j.gene.2015.03.075 · 2.08 Impact Factor