Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder

Gabor Egervari, Diana Akpoyibo, Tanni Rahman, John F. Fullard, James E. Callens, Joseph A. Landry, Annie Ly, Xianxiao Zhou, Noël Warren, Mads E. Hauberg, Gabriel Hoffman, Randy Ellis, Jacqueline-Marie N. Ferland, Michael L. Miller, Eva Keller, Bin Zhang, Panos Roussos and Yasmin L. Hurd ()
Additional contact information
Gabor Egervari: Icahn School of Medicine at Mount Sinai
Diana Akpoyibo: Icahn School of Medicine at Mount Sinai
Tanni Rahman: Icahn School of Medicine at Mount Sinai
John F. Fullard: Icahn School of Medicine at Mount Sinai
James E. Callens: Icahn School of Medicine at Mount Sinai
Joseph A. Landry: Icahn School of Medicine at Mount Sinai
Annie Ly: Icahn School of Medicine at Mount Sinai
Xianxiao Zhou: Icahn School of Medicine at Mount Sinai
Noël Warren: Icahn School of Medicine at Mount Sinai
Mads E. Hauberg: Icahn School of Medicine at Mount Sinai
Gabriel Hoffman: Icahn School of Medicine at Mount Sinai
Randy Ellis: Icahn School of Medicine at Mount Sinai
Jacqueline-Marie N. Ferland: Icahn School of Medicine at Mount Sinai
Michael L. Miller: Icahn School of Medicine at Mount Sinai
Eva Keller: Semmelweis University
Bin Zhang: Icahn School of Medicine at Mount Sinai
Panos Roussos: Icahn School of Medicine at Mount Sinai
Yasmin L. Hurd: Icahn School of Medicine at Mount Sinai

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity significantly attenuates heroin self-administration and responding for drug-paired cues in rodents. Our findings suggest that striatal FYN is an important driver of heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN a promising therapeutic target for heroin use disorder.

Date: 2020
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DOI: 10.1038/s41467-020-18114-3

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