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
ISSN1476-5578
Abstract

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.

DOI10.1038/s41380-020-00909-x
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