Cocaine-related DNA methylation in caudate neurons alters 3D chromatin structure of the IRXA gene cluster.

TitleCocaine-related DNA methylation in caudate neurons alters 3D chromatin structure of the IRXA gene cluster.
Publication TypeJournal Article
Year of Publication2020
AuthorsVaillancourt K, Yang J, Chen GG, Yerko V, Théroux J-F, Aouabed Z, Lopez A, Thibeault KC, Calipari ES, Labonte B, Mechawar N, Ernst C, Nagy C, Forné T, Nestler EJ, Mash DC, Turecki G
JournalMol Psychiatry
Date Published2020 Oct 12

Epigenetic mechanisms, like those involving DNA methylation, are thought to mediate the relationship between chronic cocaine dependence and molecular changes in addiction-related neurocircuitry, but have been understudied in human brain. We initially used reduced representation bisulfite sequencing (RRBS) to generate a methylome-wide profile of cocaine dependence in human post-mortem caudate tissue. We focused on the Iroquois Homeobox A (IRXA) gene cluster, where hypomethylation in exon 3 of IRX2 in neuronal nuclei was associated with cocaine dependence. We replicated this finding in an independent cohort and found similar results in the dorsal striatum from cocaine self-administering mice. Using epigenome editing and 3C assays, we demonstrated a causal relationship between methylation within the IRX2 gene body, CTCF protein binding, three-dimensional (3D) chromatin interaction, and gene expression. Together, these findings suggest that cocaine-related hypomethylation of IRX2 contributes to the development and maintenance of cocaine dependence through alterations in 3D chromatin structure in the caudate nucleus.

Alternate JournalMol Psychiatry
PubMed ID33046833
Grant ListR01 DA033684 / DA / NIDA NIH HHS / United States
DA033684 / / U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA) /
P01 DA047233 / DA / NIDA NIH HHS / United States