title: Active DNA demethylation in post-mitotic neurons: a reason for optimism.
abstract: Over the last several years proteins involved in base excision repair (BER) have been implicated in active DNA demethylation. We review the literature supporting BER as a means of active DNA demethylation, and explain how the various components function and cooperate to remove the potentially most enduring means of epigenetic gene regulation. Recent evidence indicates that the same pathways implicated during periods of widespread DNA demethylation, such as the erasure of methyl marks in the paternal pronucleus soon after fertilization, are operational in post-mitotic neurons. Neuronal functional identities, defined here as the result of a combination of neuronal subtype, location, and synaptic connections are largely maintained through DNA methylation. Chronic mental illnesses, such as schizophrenia, may be the result of both altered neurotransmitter levels and neurons that have assumed dysfunctional neuronal identities. A limitation of most current psychopharmacological agents is their focus on the former, while not addressing the more profound latter pathophysiological process. Previously, it was believed that active DNA demethylation in post-mitotic neurons was rare if not impossible. If this were the case, then reversing the factors that maintain neuronal identity, would be highly unlikely. The emergence of an active DNA demethylation pathway in the brain is a reason for great optimism in psychiatry as it provides a means by which previously pathological neurons may be reprogrammed to serve a more favorable role. Agents targeting epigenetic processes have shown much promise in this regard, and may lead to substantial gains over traditional pharmacological approaches.
authors: The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612, USA; Jesse Brown Veterans Affairs Medical Center, 820 South Damen Avenue (M/C 151), Chicago, IL 60612, USA. Electronic address: dgavin@psych.uic.edu.
authors: David P
authors: DP
authors: Gavin
authors: The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612, USA.
authors: Kayla A
authors: KA
authors: Chase
authors: The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612, USA; Jesse Brown Veterans Affairs Medical Center, 820 South Damen Avenue (M/C 151), Chicago, IL 60612, USA.
authors: Rajiv P
authors: RP
authors: Sharma
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology*; D019175:DNA Methylation / Q000187:drug effects / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011619:Psychotropic Drugs / Q000494:pharmacology
chemical_list: D011619:Psychotropic Drugs
keywords: 5-Hydroxymethylcytosine; 5-Methylcytosine; 5-carboxylcytosine; 5-formylcytosine; 5-hydroxymethylcytosine; 5-hydroxymethyluracil; 5-methylcytosine; 5CaC; 5FC; 5HMC; 5HMU; 5MC; AICDA; APE1; APOBEC; BDNF; BER; COMT; CpG; CpG methylation; DNA methyltransferase; DNMT; ECS; FGF; G; GADD45; H3K27; H3K9me2; HDAC; KCl; LSD1; MBD; MeCP2; N-methyl d-aspartate receptor subtype 2B; N-methyl-d-aspartic acid; NER; NMDA; NR2B; PARP1; PFC; PGC; PP1; SMUG1; T; TDG; TET; X-ray repair cross-complementing protein-1; XRCC1; activation-induced cytidine deaminase; apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like; apurinic/apyrimidinic (AP) endonuclease; base excision repair; brain-derived neurotrophic factor; catechol-O-methyltransferase; cytosine–phosphate–guanine; dimethylated lysine 9 of histone 3; electroconvulsive seizure; fibroblast growth factor; growth arrest and DNA damage; guanine; histone deacetylase; lysine 27 of histone 3; lysine-specific demethylase-1; methyl CpG binding protein 2; methyl-CpG binding domain; nucleotide excision repair; poly ADP ribose polymerase-1; potassium chloride; prefrontal cortex; primordial germ cells; protein phosphatase 1; single-strand selective monofunctional uracil-DNA glycosylase 1; ten-eleven translocation; thymidine; thymine-DNA glycosylase
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