Functional Genomic Regulation In The Brain: (Epi)Genetic Variation, Neurodevelopment and Psychiatric Disease

Abstract

Overall Abstract Epigenetic mechanisms play a role in the dynamic regulation of various genomic functions through covalent modifications to DNA and histones. These mechanisms establish and maintain cell-specific gene expression programs to orchestrate brain development, adult neurogenesis and synaptic plasticity. Given their role in the development and function of the brain, there is increasing awareness about the involvement of altered gene regulatory processes in the etiology of many neuropsychiatric phenotypes. This symposium will highlight how studies from different areas of epigenetics research can provide important insights into the molecular etiology of schizophrenia and cognitive function, and enable the identification of potential therapeutic targets. The first presentation will discuss a study of the NuRD nucleosome remodeling complex that mediates the projection of neurons across the cerebral hemispheres during development. SATB2, BCL11B and GATAD2A encode proteins within this complex and contain genome-wide significant risk SNPs for schizophrenia. Beyond these individually associated genes, this study will describe a gene set analysis of 127 genes involved in this process during cortical development that indicates strong enrichment of association signals in both schizophrenia and educational attainment GWAS data. These data point to a role for this chromatin remodeling process in the biology of schizophrenia and cognition. The second presentation will describe an analysis of dynamic DNA modifications (5mC and 5hmC) across human brain development, highlighting how the prenatal period is a time of considerable epigenomic plasticity in the brain, and the importance of neurodevelopmentally-dynamic loci in psychiatric phenotypes. It will highlight the impact of genetic variation on the epigenome during brain development showing that although most DNA methylation quantitative trait loci (mQTLs) are developmentally stable, a subset are characterized by fetal-specific effects and enriched amongst risk loci identified in recent schizophrenia GWAS. We will highlight the utility of integrating genetic and epigenetic data to fine-map GWAS regions using co-localization approaches. The third presentation will highlight results from a study of cell type-specific genome-wide maps of chromatin accessibility, which are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. This study will describe the generation and analysis of an open chromatin atlas of different cell types in the adult human brain generated across multiple brain regions. Transcription factor-gene regulome networks were generated for each cell type and brain region and subnetworks affected by schizophrenia risk loci were identified. The final presentation will describe a study of non-coding RNAs in neuronal function. This study will highlight how epigenetic processes are potential therapeutic targets in neuropsychiatric disorders and will then detail research work showing that non-coding RNAs regulate epigenetic dynamics in neuronal systems to support cognitive function.