Nucleoporins as epigenomic regulators of cardiogenesis

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PROJECT SUMMARY Nucleoporins (NUPs) are specialized proteins that comprise the nuclear pore complex, with canonical roles in nucleocytoplasmic transport and cell cycle regulation. Recent demonstration of alternative functions for NUPs has revealed a diversity of regulatory epigenomic properties critical for health and disease. Our preliminary data prioritizes a subset of NUPs associated with pathological cardiac processes, supported by clinical observations of impaired cardiogenesis correlated with dysfunctional NUP expression. For example, atrial fibrillation is a cardiac phenotype associated with NUP155 mutation, yet the precise arrhythmogenic mechanisms recruited and/or disrupted by NUP155 dysfunction remain cryptic. We propose to address this gap in knowledge through 1) assessment of potential epigenomic regulatory mechanisms driven by mammalian NUP155, and 2) examination of NUP155-driven cardiac phenotypes in a model of stem cell- derived cardiogenesis. NUP155 is anticipated to emerge as a critical factor that regulates proper establishment of cardiac electrical machinery, as well as exemplify a broader functional paradigm of NUPs as epigenomic regulators of development. The thematic scope of this project complements the cardiac feto-maternal studies proposed by the Baack group, and supports the central theme focused on examining the role of cellular pliancy regulators in disease development. Work in the Faustino lab will use the updated capacities of the Phase II Molecular Genomics and Informatics Core, whose added technologies and analytics will include high throughput sequencing pipelines (e.g., ChIP-seq, ATAC-seq), and R-script based bioinformatic software (Bioconductor hosted within a Linux OS). In addition, genome editing resources within the enhanced Core will be used. All Phase II CoBRE projects describe diverse omics and informatics needs that will be met by the increased capacities of the augmented Cores. Thus, the conceptual and technical synergies of the Phase II project cluster will build on the successful momentum of Phase I, and is anticipated to facilitate the development of Sanford Research into a robust Center of Research Excellence.