DNA Methylation of a Novel Regulatory Element Within the Tyrosine Hydroxylase Gene (TH) is Dysregulated by Chronic Cocaine Dependence in the Human Striatum

Abstract

Cocaine dependence is a chronic, relapsing disorder caused by lasting changes within the brain’s reward circuitry. Methylome-wide studies have identified multiple biological pathways that contain altered DNA methylation dynamics in the striatum of rodents; however, there is a lack of information about the involvement of DNA methylation in cocaine dependence in humans. Here, we generated genome-wide methylomic profiles for the nucleus accumbens, part of the ventral striatum, using human postmortem brains from a cohort of cocaine dependent and healthy controls (n=25 per group). In particular, we have identified hypermethylation of a cluster of CpGs within the gene body of tyrosine hydroxylase gene (TH), which contains a putative binding site for the early growth response 1 (EGR1) transcription factor. We replicated this finding in striatal tissue from an independent cohort (n=18 per group) and found it to be specific to striatal neuronal nuclei. Furthermore, this locus demonstrates enhancer activity in vitro, which is attenuated by methylation and enhanced by EGR1 overexpression. This is the first time that epigenetic dysregulation has been associated with cocaine dependence with respect to dopaminergic signaling and represents an important advancement in our understanding of drug neurobiology in humans.