We always hear about the importance of balance in our lives; work-life balance, balanced budgets, and a balanced diet, but what happens when the scales are tipped? For people struggling with schizophrenia or bipolar disorder, an imbalance of dopamine in the brain can lead to delusions or hallucinations caused by major psychosis. Although we’ve known about this delicate dopamine balancing act for decades, we still don’t understand what pushes it over the edge at the molecular level.
A new study from the lab of Viviane Labrie (Van Andel Research Institute, USA) suggests that there’s an epigenetic tug of war on chromosome 11 that falls apart in psychosis. The team isolated neuronal nuclei from post-mortem prefrontal cortex of patients with schizophrenia and bipolar disorder and performed a differential DNA methylation study with the EPIC array to find that:
- There are 18 probes that differentiate subjects who had major psychosis from controls
- Differentially methylated probes (DMPs) are enriched in regions important to embryonic development, synapse function, and immune response
- The same profile was seen in differentially expressed genes from an RNA-seq analysis of a subset of the same cohort
- 72% of DMPs are impacted by genetic variation, as determined by PsychArray-24 microarray genotyping
Two of the top psychosis-related DMPs are located in the 3’end of the insulin-like growth factor 2 (IGF2) gene, which is hypomethylated in the psychosis samples. By examining a Hi-C dataset, the talented team saw that their enhancer of interest interacts with tyrosine hydroxylase (TH), which is an important enzyme in dopamine production. They then noticed that IGF2 enhancer methylation is negatively correlated with TH protein levels in post-mortem frontal cortex. In order to dig deeper into the balancing act of this chromatin conformation relationship, they used mice with a similar Igf2 enhancer knockout (KO), where they found that:
- The TH protein is decreased in the striatum and levels of dopamine are also lower in KO mice
- RNA-seq revealed that the differentially expressed genes are enriched for cell development, immune, protein synthesis, neurodevelopment and Tnf-alpha signalling, which suggests that the mice have impaired synapse development
- By isolating synaposomes from KO mice and performing proteomic analysis with mass spectrometry, they showed that 956 proteins are dysregulated, including some related to neuro-signalling and synaptic vesicle release
The end result of this disruption to the brain’s balancing act delivers a double whammy to neurons by pulling the epigenome away from proper synapse formation and pushing it towards increased dopamine production. Hypomethylation of the IGF2 enhancer tips the scales towards increased TH expression and dopamine production.
Senior author Viviane Labrie shares “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.”
Scale over to the original article in Nature Communications, May 2019.