McGill Group for Suicide Studies, Douglas Hospital Research Center, Montreal, QC, Canada.
Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
Mol Psychiatry. 2021 Jul;26(7):3134-3151. doi: 10.1038/s41380-020-00909-x. Epub 2020 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.
表观遗传机制，如涉及 DNA 甲基化的机制，被认为介导了慢性可卡因依赖与成瘾相关神经回路中分子变化之间的关系，但在人类大脑中研究较少。我们最初使用简化代表性亚硫酸氢盐测序（RRBS）在人类死后尾状核组织中生成可卡因依赖的全基因组甲基组图谱。我们专注于同源框 A（IRXA）基因簇，其中神经元核中 IRX2 外显子 3 的低甲基化与可卡因依赖有关。我们在一个独立的队列中复制了这一发现，并在可卡因自我给药的小鼠的背侧纹状体中发现了类似的结果。使用表观基因组编辑和 3C 测定法，我们证明了 IRX2 基因体内甲基化、CTCF 蛋白结合、三维（3D）染色质相互作用和基因表达之间存在因果关系。总之，这些发现表明，IRX2 的可卡因相关低甲基化通过尾状核中 3D 染色质结构的改变，导致可卡因依赖的发展和维持。
