Nucleoporins as epigenomic regulators of cardiogenesis

项目总结 核孔蛋白(Nup)是一种特殊的蛋白质，它构成核孔复合体，在 核质转运和细胞周期调控。最近演示了NUP的替代功能 揭示了对健康和疾病至关重要的各种调控表观基因组特性。我们的预赛 数据优先排序与病理性心脏过程相关的NUP子集，并得到临床支持 心脏生成受损的观察与功能异常的NUP表达相关。例如，心房 纤颤是一种与NUP155突变相关的心脏表型，但确切的致心律失常 NUP155功能障碍所招募和/或破坏的机制仍不清楚。我们建议解决这个问题 通过1)评估潜在的表观基因组调控机制 哺乳动物NUP155，以及2)在干细胞模型中检测NUP155驱动的心脏表型。 衍生的心脏生成。NUP155预计将成为规范适当编制的关键因素 以及作为表观基因组的NUPS的更广泛的功能范例 发展的监管机构。本项目的主题范围是对心脏母婴研究的补充。 由Baack小组提出，并支持侧重于研究细胞柔韧性的作用的中心主题 疾病发展中的监管者。Faustino实验室的工作将使用第二阶段的更新能力 分子基因组学和信息学核心，其增加的技术和分析将包括高 吞吐量测序流水线(例如，芯片序列、ATAC序列)和基于R脚本的生物信息学软件 (托管在Linux操作系统中的BioConductor)。此外，增强型核心内的基因组编辑资源将 被利用。所有第二阶段的Cobre项目描述了多样化的组学和信息学需求，这些需求将由 增加了扩充核心的容量。因此，第二阶段的概念和技术协同作用 项目群组将在第一阶段成功势头的基础上再接再厉，预计将促进 将桑福德研究发展成为一个强大的卓越研究中心。

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.