Cocaine-related DNA methylation in caudate neurons alters 3D chromatin structure of the IRXA gene cluster.
Mol Psychiatry
; 26(7): 3134-3151, 2021 07.
Article
em En
| MEDLINE
| ID: mdl-33046833
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cromatina
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Família Multigênica
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Proteínas de Homeodomínio
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Metilação de DNA
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Transtornos Relacionados ao Uso de Cocaína
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Neurônios
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article