期刊
BIOLOGICAL PSYCHIATRY
卷 82, 期 11, 页码 794-805出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2017.04.013
关键词
Addiction; Chromatin looping; CTCF; DNA methylation; Histone methylation; Nucleus accumbens
资金
- National Institutes of Health [P01 DA008227, K99DA042111]
- National Alliance for Research on Schizophrenia and Depression Young Investigator Award
BACKGROUND: Exposure to drugs of abuse alters the epigenetic landscape of the brain's reward regions, such as the nucleus accumbens. We investigated how combinations of chromatin modifications affect genes that regulate responses to cocaine. We focused on Auts2, a gene linked to human evolution and cognitive disorders, which displays strong clustering of cocaine-induced chromatin modifications in this brain region. METHODS: We combined chromosome conformation capture, circularized chromosome conformation capture, and related approaches with behavioral paradigms relevant to cocaine phenotypes. Cell type-specific functions were assessed by fluorescence-activated cell sorting and viral-mediated overexpression in Cre-dependent mouse lines. RESULTS: We observed that Auts2 gene expression is increased by repeated cocaine administration specifically in D-2-type medium spiny neurons in the nucleus accumbens, an effect seen in male but not female mice. Auts2 messenger RNA expression was also upregulated postmortem in the nucleus accumbens of male human cocaine addicts. We obtained evidence that chromosomal looping, bypassing 1524 kb of linear genome, connects Auts2 to the Caln1 gene locus under baseline conditions. This looping was disrupted after repeated cocaine exposure, resulting in increased expression of both genes in D-2-type medium spiny neurons. Cocaine exposure reduces binding of CCCTC-binding factor, a chromosomal scaffolding protein, and increases histone and DNA methylation at the Auts-Caln1 loop base in the nucleus accumbens. Cell type-specific overexpression of Auts2 or Caln1 in D-2-type medium spiny neurons demonstrated that both genes promote cocaine reward. CONCLUSIONS: These findings suggest that cocaine-induced alterations of neuronal three-dimensional genome organization destabilize higher order chromatin at specific loci that regulate responses to the drug.
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