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Differential Methylation of Enhancer May Lead to Abnormal Dopamine Levels in Major Psychosis

NEW YORK (GenomeWeb) – A multi-omic analysis has found that a key enhancer may be epigenetically activated to contribute to the symptoms of major psychosis.

An international team of researchers isolated neurons from the prefrontal cortices of individuals with schizophrenia and bipolar disorder for analysis. Schizophrenia and bipolar disorder — both mental disorders characterized by periods of psychosis — affect about 100 million people across the globe.

As they reported in Nature Communications, the researchers uncovered differences in methylation at more than a dozen different sites in individuals with schizophrenia and bipolar disorder, including hypomethylation at an insulin-like growth factor 2 (IGF2) gene enhancer. This enhancer, they added, targets the tyrosine hydroxylase (TH) gene, which is involved in dopamine synthesis, an imbalance in which has been linked to the development of major psychosis. In a mouse model, changes affecting the IGF2 enhancer influence TH protein and dopamine levels, they reported.

"[H]ypomethylation of the enhancer at IGF2 may be an important contributor to the pathogenesis of psychotic symptoms," the University of Toronto's Viviane Labrie and her colleagues wrote in their paper.

They conducted an epigenome-wide association study of neuronal nuclei isolated from the frontal cortices of the brains of 29 individuals with schizophrenia, 26 individuals with bipolar disorder, and 27 controls. Eighteen regions harbored DNA methylation differences in patients with major psychosis, and these regions were enriched for involvement in embryonic development, synaptic function, and immune cell activation.

Through RNA-sequencing of a subset of these individuals, the researchers confirmed this altered DNA methylation status affected patients' transcriptomes.

Two of the top differentially methylated regions mapped to near the 3' end of the IGF2 gene, the researchers noted. IGF2 is involved in synapse development, spine maturation, and memory formation.

This hypomethylated locus overlaps with an enhancer in the adult frontal cortex. Through a Hi-C data analysis, the researchers found that the IGF2 enhancer targets the TH gene. TH, the researchers said, is the rate-limiting enzyme in dopamine production, and dopamine is dysregulated in the cortex and striatum of individuals with schizophrenia and bipolar disorder.

They added that reduced methylation at the IGF2 enhancer was associated with increased TH protein levels in the frontal cortex, supporting the notion that the enhancer influences dopamine synthesis.

Additionally, transgenic mice lacking the Igf2 enhancer exhibit a decrease in TH protein and dopamine levels in the striatum, though not in the frontal cortex. TH protein levels were 5.6 times higher in the mouse striatum, as compared to the frontal cortex. This suggested to the researchers that epigenetic disruption of IGF2 enhancer activity in neurons leads to abnormalities in dopaminergic signaling.

Through RNA-seq, the researchers found that deletion of this enhancer in mice led to an increase in Igf2 expression in the frontal cortex and striatum, but also affected the expression of other genes in those brain regions, particularly genes involved in neurodevelopment, immune response, and cell proliferation and development.

Meanwhile, mice lacking this enhancer also experienced expression changes of synaptic proteins, especially of those involved in neurosignaling and structure, and including ones already tied to psychiatric disorders like Camk2a.

Based on their findings, the researchers hypothesized that altered epigenetic control of IGF2 enhancer activity could influence both the dopamine-mediated symptoms of psychosis as well as the synaptic structural alterations seen in major psychosis.