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.
Highlights
70–80% of cytosines in CpG dinucleotides are methylated in human somatic cells
The fact that cytosine analogs are incorporated into DNA in nondividing cells at a high enough rate to substantially trap DNA methyltransferases (DNMT) implies a mechanism of demethylation that involves replacing entire cytosine bases, such as a base excision repair (BER) process rather than removing methyl groups from cytosines
These findings are in accord with data indicating that GADD45b is a positive regulator of neurotrophic factors such as Brain-Derived Neurotrophic Factor (BDNF), Fibroblast Growth Factor (FGF), and neurogenesis, in the hippocampus as a result of its role in active demethylation (Ma et al, 2009b)
Summary
70–80% of cytosines in CpG dinucleotides are methylated in human somatic cells. DNA methylation gene silencing has been shown to be important for maintaining cellular subtypes, and contributes to sustaining functional identities, including stabilizing neuronal interactions (Bird, 2002; Cortese et al, 2011; De Carvalho et al, 2010; Deaton et al, 2011; Iwamoto et al, 2011; Levenson et al, 2006). DNMT1 and DNMT3a double knockout mice have been shown to have deficits in learning and memory (Feng et al, 2010), while restoration of DNMT3a2 levels in aged mice leads to improved memory (Oliveira et al, 2012) Based on these studies it appears in general DNA methylation changes are important for memory formation. The importance of recent insights into the DNA demethylation pathway cannot be understated as this raises the possibility that neurons containing a gene expression profile that contributes to mental illness encoded by DNA methylation can be reprogrammed using epigenetic tools
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