Nucleoporins as epigenomic regulators of cardiogenesis

项目概要 核孔蛋白 (NUP) 是构成核孔复合物的特殊蛋白质，在 核细胞质运输和细胞周期调节。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多种表观基因组调控特性。我们的初步 数据优先考虑与病理性心脏过程相关的 NUP 子集，并得到临床支持 心脏发生受损与 NUP 表达功能失调相关的观察结果。例如，心房 颤动是一种与 NUP155 突变相关的心脏表型，但精确的致心律失常 NUP155 功能障碍所招募和/或破坏的机制仍然是神秘的。我们建议解决这个问题 知识差距通过1）评估潜在的表观基因组调控机制驱动 哺乳动物 NUP155，以及 2) 在干细胞模型中检查 NUP155 驱动的心脏表型 衍生的心脏发生。 NUP155 预计将成为调节适当建立的关键因素 心脏电机的功能，并举例说明了 NUP 作为表观基因组的更广泛的功能范式 发展的监管者。该项目的主题范围补充了胎儿母体心脏研究 由 Baack 小组提出，并支持集中于检查细胞柔顺性作用的中心主题 疾病发展的调节者。 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，其附加技术和分析将包括高 通量测序流程（例如 ChIP-seq、ATAC-seq）和基于 R 脚本的生物信息学软件 （Bioconductor 托管在 Linux 操作系统中）。此外，增强核心内的基因组编辑资源将 被使用。所有第二阶段 CoBRE 项目都描述了不同的组学和信息学需求，这些需求将由 增强核心的容量增加。因此，第二阶段的概念和技术协同作用 项目群将以第一阶段的成功势头为基础，预计将促进 将桑福德研究中心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.