Open AccessCocaine-related DNA methylation in caudate neurons alters 3D chromatin structure of the IRXA gene cluster
Author(s) -
Kathryn Vaillancourt,
Jennie Yang,
Gary G. Chen,
Volodymyr Yerko,
Jean-François Théroux,
Zahia Aouabed,
Alberto J. López,
Kimberly C. Thibeault,
Erin S. Calipari,
Benoît Labonté,
Naguib Mechawar,
Carl Ernst,
Corigy,
Thierry Forné,
Eric J. Nestler,
Deborah C. Mash,
Gustavo Turecki
Publication year - 2020
Publication title -
molecular psychiatry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.071
H-Index - 213
eISSN - 1476-5578
pISSN - 1359-4184
DOI - 10.1038/s41380-020-00909-x
Subject(s) - dna methylation , chromatin , epigenetics , epigenome , biology , histone , chromatin remodeling , genetics , gene , gene expression
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.