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Active DNA demethylation in post-mitotic neurons: a reason for optimism
David P Gavin1, Kayla A Chase2, Rajiv P Sharma1
1The 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.
Neuropharmacology
|August 21, 2013
Summary
Base excision repair (BER) proteins drive active DNA demethylation, reprogramming dysfunctional neurons. This epigenetic pathway offers new hope for treating chronic mental illnesses like schizophrenia by targeting neuronal identity.
Area of Science:
- Epigenetics
- Neuroscience
- Molecular Biology
Background:
- DNA methylation is a key epigenetic regulator of neuronal identity.
- Chronic mental illnesses may involve dysfunctional neuronal identities maintained by DNA methylation.
- Active DNA demethylation in post-mitotic neurons was previously considered unlikely.
Purpose of the Study:
- To review the role of base excision repair (BER) proteins in active DNA demethylation.
- To explain the mechanism of BER-mediated DNA demethylation in neurons.
- To discuss the therapeutic potential of targeting epigenetic processes in psychiatry.
Main Methods:
- Literature review of studies on BER and DNA demethylation.
- Analysis of evidence for BER pathway operation in post-mitotic neurons.
- Discussion of implications for neuronal identity and mental illness.
Main Results:
- BER proteins are involved in active DNA demethylation, removing epigenetic marks.
- The BER pathway is active in post-mitotic neurons, challenging previous assumptions.
- This pathway can reprogram dysfunctional neuronal identities.
Conclusions:
- Active DNA demethylation via BER in neurons provides a mechanism for reversing pathological changes.
- Targeting epigenetic processes offers a promising therapeutic strategy for mental illnesses.
- This approach may lead to significant advancements over traditional psychopharmacology.
Keywords:
5-Hydroxymethylcytosine5-Methylcytosine5-carboxylcytosine5-formylcytosine5-hydroxymethylcytosine5-hydroxymethyluracil5-methylcytosine5CaC5FC5HMC5HMU5MCAICDAAPE1APOBECBDNFBERCOMTCpGCpG methylationDNA methyltransferaseDNMTECSFGFGGADD45H3K27H3K9me2HDACKClLSD1MBDMeCP2N-methyl d-aspartate receptor subtype 2BN-methyl-d-aspartic acidNERNMDANR2BPARP1PFCPGCPP1SMUG1TTDGTETX-ray repair cross-complementing protein-1XRCC1activation-induced cytidine deaminaseapolipoprotein B mRNA editing enzyme, catalytic polypeptide-likeapurinic/apyrimidinic (AP) endonucleasebase excision repairbrain-derived neurotrophic factorcatechol-O-methyltransferasecytosine–phosphate–guaninedimethylated lysine 9 of histone 3electroconvulsive seizurefibroblast growth factorgrowth arrest and DNA damageguaninehistone deacetylaselysine 27 of histone 3lysine-specific demethylase-1methyl CpG binding protein 2methyl-CpG binding domainnucleotide excision repairpoly ADP ribose polymerase-1potassium chlorideprefrontal cortexprimordial germ cellsprotein phosphatase 1single-strand selective monofunctional uracil-DNA glycosylase 1ten-eleven translocationthymidinethymine-DNA glycosylase
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