Nuclear pore complex proteins-directed 3D nuclear architecture in neural development and disease

神经发育和疾病中核孔复合蛋白导向的 3D 核结构

• 批准号: 507965872
• 负责人: Dr. Anna Poetsch
• 金额: --
• 依托单位: Institut für Biochemie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/507965872?language=en
• 关键词: Nuclear; pore; complex; proteins; directed

3D chromatin organization underlies lineage-specific gene expression and genome instability, which both are affected by nuclear structural proteins such as the nuclear pore complex. Recent studies and our pilot data indicate that nuclear pore complex proteins (Nups) directly or indirectly interact with chromatin and provide a structural scaffold for epigenetic regulators, transcription factors and DNA repair. Furthermore, Nup153, one of Nups was found to interact with the CTCF/cohesion complex to possibility organize topology associated domains (TAD). Our preliminary genomic analyses also indicate prominent roles for Nup153 in topological and directional gene regulation. This accumulating evidence suggests mechanisms of chromatin reorganization around pores to balance gene regulation and genome stability. Still, causal relationships among the accumulated damage on Nups, mechanisms behind Nups-directed 3D genome architecture, and its impact on regulation and genome instability remain largely elusive, especially in neural cells, where we expect high impact on disease development. In the proposed project, by combining interdisciplinary expertise, we will address, 1) how 3D genome organization at the nuclear pores is reorganized during neural differentiation, 2) to what extent disruption of Nups leads to disorganization of 3D chromatin organization, 3) what the spatial relationship of the balance between genome instability and Nups-directed 3D nuclear architecture is. Understanding spatio-temporal mechanisms underlying the organization of 3D genome-architecture at the nuclear pore is vital to unravel how cell type-specific epigenetic programs are maintained, while also preserve stability. Deregulation of these mechanisms can lead to dysfunctional neurodevelopment with cancer and neurodevelopmental diseases as potential consequences. To this end, using neural cells at different developmental stages as a model, we will employ multi-omics approaches to unravel relationships of multilayered epigenetic characteristics around nuclear pores. By integrating HiChIP, ChIP-seq, ATAC-seq, AP-seq, and END-seq, we will characterize changes of nuclear architecture at nuclear pores in 3D-chromatin interactions, binding of epigenetic regulators, chromatin accessibility, and DNA damage, upon differentiation and loss of Nup153. We will also interrogate the spatial relationship between identified changes in chromatin architecture and genomic mutations in cancer and neurodevelopmental disorders. The analyses will uncover the risk of genomic vulnerability associated with nuclear pores.

3D 染色质组织是谱系特异性基因表达和基因组不稳定性的基础，两者都受到核孔复合物等核结构蛋白的影响。最近的研究和我们的试点数据表明，核孔复合蛋白 (Nups) 直接或间接与染色质相互作用，并为表观遗传调节因子、转录因子和 DNA 修复提供结构支架。此外，Nup153（Nups 之一）被发现与 CTCF/内聚复合体相互作用，以可能组织拓扑相关域（TAD）。我们的初步基因组分析还表明 Nup153 在拓扑和定向基因调控中发挥着重要作用。这些不断积累的证据表明，孔周围的染色质重组机制可以平衡基因调控和基因组稳定性。尽管如此，Nups 累积损伤、Nups 导向的 3D 基因组结构背后的机制及其对调控和基因组不稳定性的影响之间的因果关系仍然很大程度上难以捉摸，特别是在神经细胞中，我们预计神经细胞对疾病的发展有很大影响。在拟议的项目中，通过结合跨学科专业知识，我们将解决：1）核孔处的 3D 基因组组织在神经分化过程中如何重组，2）Nups 的破坏在多大程度上导致 3D 染色质组织的混乱，3）基因组不稳定性和 Nups 导向的 3D 核结构之间的平衡的空间关系是什么。了解核孔 3D 基因组结构组织背后的时空机制对于阐明细胞类型特异性表观遗传程序如何维持并同时保持稳定性至关重要。这些机制的放松管制可能导致神经发育功能障碍，并可能导致癌症和神经发育疾病。为此，我们将利用不同发育阶段的神经细胞作为模型，采用多组学方法来揭示核孔周围多层表观遗传特征的关系。通过整合 HiChIP、ChIP-seq、ATAC-seq、AP-seq 和 END-seq，我们将表征在 Nup153 分化和丢失时，3D 染色质相互作用、表观遗传调节因子的结合、染色质可及性和 DNA 损伤中核孔核结构的变化。我们还将探讨已识别的染色质结构变化与癌症和神经发育障碍的基因组突变之间的空间关系。这些分析将揭示与核孔相关的基因组脆弱性风险。