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Active DNA Demethylation in Post-Mitotic Neurons: A Reason for Optimism

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journal contribution
posted on 02.12.2013 by David P. Gavin, Kayla A. Chase, Rajiv P. Sharma
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.

Funding

This work was supported in part by a NARSAD Young Investigator Award donation from The Family of Joseph M. Evans and the Department of Veterans Affairs (Merit Review Grant; Career Development Award (CDA-2)) (DPG) and National Institutes of health (NIH) R01 MH094358 grant (RPS).

History

Publisher Statement

NOTICE: This is the author’s version of a work that was accepted for publication in Neuropharmacology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neuropharmacology, 2013. DOI: 10.1016/j.neuropharm.2013.07.036

Publisher

Elsevier

Language

en_US

issn

1873-7064

Issue date

01/08/2013

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