Scientists at the Van Andel Research Institute (VARI) believe that a newly-identified epigenetic hotspot for schizophrenia and bipolar disorder may give scientists a fresh path forward for devising more effective treatments and biomarker-based screening strategies. While effective medications do exist, they often have side effects such as apathy, weight gain, and dyskinesias that typically are associated with Parkinson’s disease. Currently, there are no effective biomarkers for screening and tracking progression of either disorder.
The team published its study “Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosis”) in Nature Communications.
“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,” the investigators wrote.
“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.”
“We’ve known since the 1970s that the effectiveness of antipsychotic medications is directly related to their ability to block dopamine signaling. However, the exact mechanism that sparks excessive dopamine in the brain and that leads to psychotic symptoms has been unclear,” said Viviane Labrie, PhD, assistant professor at VARI and corresponding author of the study, which appears in the May 3 edition of Nature Communications. “We now have a biological explanation that could help make a real difference for people with these disorders.”
Labrie and her collaborators found a cluster of epigenetic marks that ratchets up dopamine production while simultaneously scrambling the brain’s synapses. The result is a major shake-up of the brain’s organization and chemical balance that fuels symptoms of psychosis.
“What we’re seeing is a one-two punch—the brain is being flooded with too much dopamine and at the same time it is losing these critical neural connections,” Labrie said. “Like many other neurological disorders, schizophrenia and bipolar disorder often have early, or prodromal, phases that begin years before obvious symptoms. It is our hope that our findings may lead to new biomarkers to screen for risk, which would then allow for earlier intervention.”
The team took a comprehensive look at DNA derived from brain cells of people with either schizophrenia or bipolar disorder and compared them to healthy controls. Their analyses revealed a cluster of epigenetic marks, which switch genes on and off, in an enhancer at a gene called IGF2, a critical regulator of synaptic development. Enhancers are stretches of DNA that help activate genes and can be major players in the development of diseases in the brain and other tissues.
This enhancer also controls the activity of the nearby called tyrosine hydroxylase gene, which keeps dopamine in check. When the enhancer is epigenetically switched on, production of dopamine becomes dysregulated, resulting in too much of the chemical in the brain.
Taken together, molecular changes at this site may explain why psychosis brought on by dopamine frequently is accompanied by a disruption of brain synapses, a devastating double-hit that promotes symptoms.
The study controlled for genetic factors, sex, ethnicity, treatment history and lifestyle influences such as smoking, and the results were validated in experimental models of the disease.
“We used cutting-edge computational strategies to understand the events occurring in brain cells that underlie psychiatric disorders,” said Shraddha Pai, PhD, a postdoctoral fellow at the University of Toronto and the study’s first author. “Our results were strengthened by additional studies in disease models. This comprehensive approach lends weight to our findings, which we believe will propel additional groundbreaking investigations into this enhancer at the IGF2 gene.”
