Abstract
Addiction is a chronically relapsing neuropsychiatric disease that occurs in some, but not all, individuals who use substances of abuse. Relatively little is known about the mechanisms which contribute to individual differences in susceptibility to addiction. Neural gene expression regulation underlies the pathogenesis of addiction, which is mediated by epigenetic mechanisms, such as DNA modifications. A growing body of work has demonstrated distinct DNA epigenetic signatures in brain reward regions that may be associated with addiction susceptibility. Furthermore, factors that influence addiction susceptibility are also known to have a DNA epigenetic basis. In the present review, we discuss the notion that addiction susceptibility has an underlying DNA epigenetic basis. We focus on major phenotypes of addiction susceptibility and review evidence of cell type-specific, time dependent, and sex biased effects of drug use. We highlight the role of DNA epigenetics in these diverse processes and propose its contribution to addiction susceptibility differences. Given the prevalence and lack of effective treatments for addiction, elucidating the DNA epigenetic mechanism of addiction vulnerability may represent an expeditious approach to relieving the addiction disease burden.
Highlights
DNA cytosine methylation is a major epigenetic modification in which methyl groups are covalently bound to the 5-carbon position of cytosine bases by DNA methyltransferases (DNMTs; e.g., DNMT1, DNMT3A, and DNMT3B) (Jaenisch and Bird, 2003)
Cytosine methylation is considerably stable, it can be oxidized by the ten-eleven translocation methylcytosine dioxygenases (TETs; TET1, TET2, and TET3), which convert mC into hydroxymethylcytosine. hmC can persist as a stable epigenetic modification or be further oxidized by TETs into formylcytosine and carboxylcytosine
The results suggest that DNA methylation remodeling in the brain may be an index of alcohol use disorder (AUD) susceptibility, and DNA methylation changes in discrete genes in the nucleus accumbens (NAc) may influence specific alcohol drinking phenotypes associated with variable risks for developing AUD
Summary
DNA cytosine methylation (mC) is a major epigenetic modification in which methyl groups are covalently bound to the 5-carbon position of cytosine bases by DNA methyltransferases (DNMTs; e.g., DNMT1, DNMT3A, and DNMT3B) (Jaenisch and Bird, 2003). Cytosine methylation is considerably stable, it can be oxidized by the ten-eleven translocation methylcytosine dioxygenases (TETs; TET1, TET2, and TET3), which convert mC into hydroxymethylcytosine (hmC). HmC can persist as a stable epigenetic modification or be further oxidized by TETs into formylcytosine (fC) and carboxylcytosine (caC). During active DNA demethylation, fC and caC are excised and replaced with unmethylated cytosine through base excision repair (BER) mechanisms (Wu and Zhang, 2014; Xu and Bochtler, 2020). Together, these processes comprise and regulate DNA epigenetic dynamics in the brain
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