Cocaine-Induced Chromatin Modifications Associate With Increased Expression and Three-Dimensional Looping of Auts2

• Published in: Biological psychiatry (1969) 2017-12, Vol.82 (11), p.794-805
• Main Authors: Engmann, Olivia, Labonté, Benoit, Mitchell, Amanda, Bashtrykov, Pavel, Calipari, Erin S, Rosenbluh, Chaggai, Loh, Yong-Hwee E, Walker, Deena M, Burek, Dominika, Hamilton, Peter J, Issler, Orna, Neve, Rachael L, Turecki, Gustavo, Hurd, Yasmin, Chess, Andrew, Shen, Li, Mansuy, Isabelle, Jeltsch, Albert, Akbarian, Schahram, Nestler, Eric J
• Format: Article
• Language: English
• Subjects: Addiction; Adolescent; Adult; Aged; Aged, 80 and over; Animals; Cell Line, Tumor; Chromatin - drug effects; Chromatin looping; Cocaine - administration & dosage; Cohort Studies; Conditioning, Operant - drug effects; CTCF; Cytoskeletal Proteins; DNA methylation; DNA Methylation - drug effects; Dopamine Uptake Inhibitors - administration & dosage; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Histone methylation; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Models, Molecular; Molecular Conformation; Neuroblastoma - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nucleus accumbens; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Psychiatry; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1 - genetics; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D2 - metabolism; Transcription Factors; Young Adult
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2017.04.013

Abstract 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 D2 -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 D2 -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 D2 -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.