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

Molecular psychiatry 2021 Jul

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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. © 2020. The Author(s), under exclusive licence to Springer Nature Limited.

Citation

Kathryn Vaillancourt, Jennie Yang, Gary G Chen, Volodymyr Yerko, Jean-François Théroux, Zahia Aouabed, Alberto Lopez, Kimberly C Thibeault, Erin S Calipari, Benoit Labonté, Naguib Mechawar, Carl Ernst, Corina Nagy, Thierry Forné, Eric J Nestler, Deborah C Mash, Gustavo Turecki. Cocaine-related DNA methylation in caudate neurons alters 3D chromatin structure of the IRXA gene cluster. Molecular psychiatry. 2021 Jul;26(7):3134-3151