YBX1-Mediated DNA Methylation-Dependent SHANK3 Expression in PBMCs and Developing Cortical Interneurons in Schizophrenia.

Abstract

Schizophrenia (SCZ) is a severe psychiatric and neurodevelopmental disorder. The pathological process ofSCZ starts early during development, way before the first onset of psychotic symptoms. DNA methylation plays an important role in regulating gene expression and dysregulated DNA methylation is involved in the pathogenesis of various diseases. The methylated DNA immunoprecipitation-chip (MeDIP-chip) is performed to investigate genome-wide DNA methylation dysregulation in peripheral blood mononuclear cells (PBMCs) of patients with first-episode SCZ (FES). Results show that the SHANK3promoter is hypermethylated, and this hypermethylation (HyperM) is negatively correlated with the cortical surface area in the left inferior temporal cortex and positively correlated with the negative symptom subscores in FES. The transcription factor YBX1is further found to bind to the HyperM region of SHANK3promoter in induced pluripotent stem cells (iPSCs)-derived cortical interneurons (cINs) but not glutamatergic neurons. Furthermore, a direct and positive regulatory effect of YBX1on the expression of SHANK3is confirmed in cINs using shRNAs. In summary, the dysregulated SHANK3expression in cINs suggests the potential role of DNA methylation in the neuropathological mechanism underlying SCZ. The results also suggest that HyperM of SHANK3in PBMCs can serve as a potential peripheral biomarker of SCZ.