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

Molecular Psychiatry volume 26, pages 3134–3151 (2021)Cite this article

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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.

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Fig. 1: Widespread changes in DNA methylation associated with chronic cocaine dependence in the human caudate nucleus.
Fig. 2: IRX2 is hypomethylated in the caudate nucleus.
Fig. 3: IRX2 expression is increased in cocaine use disorder and is related to exon 3 methylation in cells.
Fig. 4: Long-range chromatin structure of the IRXA gene cluster is impacted by methylation.
Fig. 5: A model for cocaine sensitivity of 3D chromatin organization at the IRXA gene cluster.

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Acknowledgements

We are deeply grateful to the families of the subjects used in this study. We would also like to acknowledge the teams of technicians at the Miami Brain Endowment BankTM and the Douglas Bell Canada Brain Bank, and the bioinformaticians who have worked on these data (Alpha Diallo, Raphaël Poujol and Alexandre Bramoulle). This work was supported by a Canadian Institute of Health Research Doctoral Fellowship awarded to KV, National Institute of Drug Abuse Grants DA033684 awarded to GT and DCM, R00 DA04211 to ESC, and P01 DA047233 to EJN, and grants from the Whitehall Foundation, the Edward Mallinckrodt Jr., Foundation, and the Brain and Behavior Research Foundation to ESC.

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Authors and Affiliations

  1. McGill Group for Suicide Studies, Douglas Hospital Research Center, Montreal, QC, Canada

    Kathryn Vaillancourt, Jennie Yang, Gary G. Chen, Volodymyr Yerko, Jean-François Théroux, Zahia Aouabed, Naguib Mechawar, Corina Nagy & Gustavo Turecki

  2. Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada

    Kathryn Vaillancourt, Naguib Mechawar, Corina Nagy & Gustavo Turecki

  3. Departments of Pharmacology, Molecular Physiology and Biophysics, and Psychiatry and Behavioral Sciences, Vanderbilt Center for Addiction Research; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA

    Alberto Lopez, Kimberly C. Thibeault & Erin S. Calipari

  4. Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Erin S. Calipari, Benoit Labonté & Eric J. Nestler

  5. Department of Psychiatry, McGill University, Montreal, QC, Canada

    Naguib Mechawar, Carl Ernst & Gustavo Turecki

  6. Institute de Génétique Moléculaire de Montpellier, CNRS, Université de Montpellier, Montpellier, France

    Thierry Forné

  7. Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA

    Deborah C. Mash

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  1. Kathryn Vaillancourt
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  2. Jennie Yang
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Contributions

Manuscript preparation: KV; experimental design and data collection: KV, JY, GGC; data analysis: KV, CE, TF, J-FT, ZA; animal experiments: AL, KCT, BL; resources and support: EJN, ESC, CN, DCM, GT.

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Correspondence to Gustavo Turecki.

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Vaillancourt, K., Yang, J., Chen, G.G. et al. Cocaine-related DNA methylation in caudate neurons alters 3D chromatin structure of the IRXA gene cluster. Mol Psychiatry 26, 3134–3151 (2021). https://doi.org/10.1038/s41380-020-00909-x

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