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Nat Commun. 2019 May 3;10(1):2046. doi: 10.1038/s41467-019-09786-7.

Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosis.

Author information

1
The Donnelly Centre, University of Toronto, Toronto, M5S 3E1, ON, Canada. shraddha.pai@utoronto.ca.
2
The Centre for Addiction and Mental Health, Toronto, M5T 1R8, ON, Canada. shraddha.pai@utoronto.ca.
3
Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, 49503, MI, USA.
4
Krembil Family Epigenetics Laboratory, Centre for Addiction and Mental Health, Toronto, M5T 1R8, ON, Canada.
5
Center for Epigenetics, Van Andel Research Institute, Grand Rapids, 49503, MI, USA.
6
Institute of Biotechnology, Life Sciences Center, Vilnius University, LT-10257, Vilnius, Lithuania.
7
Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, 49503, MI, USA. viviane.labrie@vai.org.
8
Krembil Family Epigenetics Laboratory, Centre for Addiction and Mental Health, Toronto, M5T 1R8, ON, Canada. viviane.labrie@vai.org.
9
Division of Psychiatry and Behavioral Medicine, College of Human Medicine, Michigan State University, Grand Rapids, 49503, MI, USA. viviane.labrie@vai.org.

Abstract

Impaired neuronal processes, including dopamine imbalance, are central to the pathogenesis of major psychosis, but the molecular origins are unclear. Here we perform a multi-omics study of neurons isolated from the prefrontal cortex in schizophrenia and bipolar disorder (n = 55 cases and 27 controls). DNA methylation, transcriptomic, and genetic-epigenetic interactions in major psychosis converged on pathways of neurodevelopment, synaptic activity, and immune functions. We observe prominent hypomethylation of an enhancer within the insulin-like growth factor 2 (IGF2) gene in major psychosis neurons. Chromatin conformation analysis revealed that this enhancer targets the nearby tyrosine hydroxylase (TH) gene responsible for dopamine synthesis. In patients, we find hypomethylation of the IGF2 enhancer is associated with increased TH protein levels. In mice, Igf2 enhancer deletion disrupts the levels of TH protein and striatal dopamine, and induces transcriptional and proteomic abnormalities affecting neuronal structure and signaling. Our data suggests that epigenetic activation of the enhancer at IGF2 may enhance dopamine synthesis associated with major psychosis.

PMID:
31053723
PMCID:
PMC6499808
DOI:
10.1038/s41467-019-09786-7
[Indexed for MEDLINE]
Free PMC Article

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