Genomic Determinants Of miRNA Dysregulation In Schizophrenia

Abstract

Small non-coding miRNA use homology based target interactions to guide ribonucleoprotein complexes influencing the intracellular fate of mRNA. These molecules have emerged as significant players in the regulation of brain development and neural function. Postmortem investigations of cortical miRNA expression suggest these molecules are dysregulated in schizophrenia and there is substantial genetic support for their role in the disorder, particularly the genome wide associated MIR137. This is further supported by the enrichment of rare sequence and structural variants affecting miRNA genes, their biogenesis machinery and target genes. These molecules are also key epigenomic mediators of environmental exposures associated with psychiatric disorders. Understanding the mechanisms that influence the pattern of miRNA expression during brain development, the response to environmental exposures and in schizophrenia will be important for developing interventions that can modify their activity and the pathophysiology of the pathways they regulate.In this study, we dissected cortical grey matter from the dorsolateral prefrontal cortex (DLPFC) and analysed schizophrenia-associated expression of coding and long non-coding RNA using RNA-Seq. The results suggest that dysregulation of small RNA in the disorder is influenced by several factors including genomic and epigenomic changes in the miRNA biogenesis pathway as well as more specific changes in long non-coding RNA that can interact and sequester miRNA. To further understand the functional significance of these interactions we are using transgenic human SH-SY5Y cell culture and rat models to explore the influence of these molecules to act as small RNA regulators.This work suggests that schizophrenia is associated with changes in miRNA expression caused by a variety of genomic and epigenomic mechanism, both broad and specific, that modulate gene networks important for brain development and connectivity. A better understanding of these networks and their patterns of disruption in individuals will provide an opportunity for targeted interventions with high potency against these changes that play a significant role in the neuropathology of the disorder.