Out with the old and in with the new – the role of circular RNAs in psychiatric disorders

Speaker: Nikolaos Mellios, M.D., Ph.D.
Affiliation: Assistant Professor, Department of Neurosciences, University of New Mexico

Date: April 26, 2017

Talk title: Out with the old and in with the new – the role of circular RNAs in psychiatric disorders

Abstract: Schizophrenia (SCZ) and Bipolar disorder (BD) are heterogeneous psychiatric disorders with severe socioeconomic impacts and unknown pathogenesis, despite the plethora of genomics and genetic studies focused on protein-coding genes. However, the emerging consensus is that protein-coding genes are only the tip of the iceberg of the mammalian transcriptome, given the plethora of actively transcribed non-coding RNAs (ncRNAs). Circular RNAs (circRNAs) are a novel category of ncRNAs that are derived from the back-splicing and covalent joining of exons, yet lack the capacity to become translated into protein. Recent studies have suggested that circRNAs are enriched in the brain, are preferentially generated from brain plasticity-associated genes, and are abundant in dendrites and synapses. However, very little is known about the function of circRNAs in the human brain and their potential involvement in neuropsychiatric disease. Here we carried out systematic profiling of circRNA expression in a large cohort of human postmortem brains from subjects with SCZ and BD disorder and uncovered a subset of differentially expressed circRNAs produced from genes with known links to synaptic plasticity and neuronal excitability. We validated the expression of psychiatric disease-altered circRNAs in human postmortem brain with qRT-PCR and uncovered a subset of circRNAs that were also dysregulated in induced pluripotent stem cell (iPSC)-derived human neuronal progenitor and immature neuronal cultures from subjects with BD and SCZ. In silico analysis of RNA-Binding proteins (RBPs) that could bind to psychiatric disease-associated circRNAs revealed potential interactions with RBPs that affect alternative splicing and dendritic and synaptic trafficking. Ongoing experiments using circRNA shRNA knockdown in iPSC neuronal cultures are attempting to elucidate the function of SCZ- and BD-associated circRNAs in human neuronal development and maturation and their interplay with RBPs and disease-related molecular pathways. Collectively, our experiments will shed light into the unexplored role of circRNAs in brain function and disease.