Transcriptional alterations of protein-coding and non-coding RNAs may be a common intermediate phenotype of both, genetic and environmental contribution to schizophrenia (SZ). Evidence from studies on micro RNAs and long non-coding RNAs suggest a profound influence of non-coding RNAs (ncRNAs) on brain function in health and disease. Beyond that, the function of the non-coding transcriptome remains for the most part unknown. Circular RNAs (circRNAs) are abundant non-coding RNAs that may have a regulatory role in transcription, translation and other cellular functions. Given their enrichment in the brain, their dynamic expression across development and in response to neuronal activation, it is conceivable that circRNAs may have a functional role in SZ. However, little is known about expression and function of circRNAs in normal human brain tissue and their relevance and function in SZ. Supported by preliminary data, our central hypotheses are that circRNAs show a region-, sex- and disease-specific expression profile in the brain and that circRNAs play a causal role in transcriptomic and proteomic changes in SZ. We will test these two hypotheses through two specific aims:
Specific Aim 1 will expand our robust preliminary dataset on circLARP1B probing its region- and sex-specific expression profile.
This aim will also test the hypothesis that circLARP1B is an upstream regulatory element of the RNA-binding protein LARP1B, which presumably controls SZ-specific molecular pathways through an interaction with distinct linear target mRNAs. Thus, we will expand our preliminary findings and investigate the molecular function of circLARP1B, a circRNA that shows a robust dysregulation in SZ.
Specific Aim 2 will assess circRNA and linear RNA expression in the dorsolateral prefrontal cortex and anterior cingulate cortex in an extended sample of subjects with SZ and the Common Mind RNAseq database with ~1000 samples. Here, we will test the hypothesis that additional circRNAs from loci previously implicated in SZ are differentially expressed in regions known to play a key role in SZ. We will provide evidence for a functional role of circRNAs in pathways implicated in the pathophysiology of SZ. Thus, we will expand our preliminary findings and investigate the region- and sex-specific expression and function of circRNAs in pathways altered in SZ. The significance and potential impact of this proposal lays in the fact that knowledge on the expression and function of circRNAs in the healthy and diseased human brain is sparse. By generating data on region- and sex-specific circRNA expression and molecular function of circRNAs reproducibly dysregulated in SZ, we obtain preliminary data supporting an in-depth study of the molecular function of circRNAs in interaction with known genetic, epigenetic, transcriptional and proteomic alterations in SZ as part of a future R01 proposal. This will provide novel insights into the contribution of the non-coding transcriptome to the development of SZ, and may open new avenues for the cure of this devastating condition.
The proposed research is highly relevant to public health because the discovery of functional non-coding circular RNAs in post-mortem human brain tissue of individuals with schizophrenia healthy donors will provide crucial insights into the regulation of the human genome and the underlying biological mechanisms of psychiatric disorders. This will provide conceptually new ways to think about the pathophysiology of mental disorders and prevention and therapy strategies. Thus, the project is relevant to the NIMH/NIH's mission in that it seeks fundamental knowledge about the nature of mental disorders, their development and the application of that knowledge to cure and prevent mental health disorders.
