Genomics of DNA repair in the brain

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Maintaining genome fidelity is an essential process, especially in tissues such as the brain, which are exposed to elevated levels of DNA damage due to high energy consumption. DNA repair genes have been extensively studied in non-neural cell types and lines. However, a significant knowledge gap exists in the involvement and regulation of DNA repair processes in the human brain. Advances in stem cell and genomic methodologies, however, are opening new avenues to address these gaps. Stem cell derived neural models recapitulate human biology and can be coupled with functional genomic screens to understand important genes in these systems. Further, large scale neurogenomic databases continue to grow and contain diverse genomic information. Since the brain is a complex tissue, harnessing these developments to study DNA repair in the brain can offer important insights into how these complex pathways are regulated in unique cell types. Objectives: The long-term objective of my research program is to understand the fundamental biology of DNA repair in the brain. To elucidate this, I have developed a two-pronged approach that will make use of the following platforms: bioinformatic tools (i.e., computational analyses) and in vitro models (i.e., human stem cell-derived neural models). The following short-term objectives will therefore be implemented: Objective 1: Perform bioinformatic analyses of high throughput functional genomic screens and repositories to understand and prioritize brain-relevant DNA repair genes Objective 2: Identify neural cell type specific biological processes involved in DNA repair in the brain The computational analyses will help us understand essential DNA repair-related genes and processes in the brain. These results will feed into validation experiments that will assess the impact of gene knockdown in human brain cell types at the level of gene expression to understand the key biological processes that regulate these genes. Using computational analyses to select DNA repair genes for functional follow up (i.e., bioinformatic prioritization), provides a cost-efficient and effective mechanism to study brain-related DNA-repair genes in greater detail. Impact: Developing innovative bioinformatics and functional genomics platforms will identify important DNA repair genes in the brain and determine their unique genomic characteristics. Functional experiments will assist in ascertaining the biological mechanisms underlying how they are regulated in understudied human brain cells. These findings will be especially relevant for the fields of genomics and neuroscience. HQP will be trained in latest bioinformatics and in vitro methods including neural models. These skills will equip them for careers in academia and industry. Enhancing the Canadian training capacity for these valuable skills, while promoting diversity in genomics and DNA repair biology, will also make a significant impact to the natural sciences.