Dissecting the principles guiding CTCF condensate formation in cellular ageing

解析细胞衰老过程中 CTCF 冷凝物形成的指导原则

• 批准号: 506296585
• 负责人: Professor Dr. Argyris Papantonis
• 金额: --
• 依托单位: Institut für Pathologie
• 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/506296585?language=en
• 关键词: Dissecting; principles; guiding; CTCF; condensate

Exhaustion of the replicative potential of human cells signals their commitment to an irreversible state of cell cycle arrest known as senescence. Entry into senescence, where cells remain metabolically active, is also accompanied by dramatic changes in gene expression and 3D chromatin architecture. The most notable of these changes is the clustering of CTCF – a key organizer of 3D chromatin domains – into large senescence-induced condensates. Although phase separation-type forces have now been implicated in the formation of nuclear bodies (e.g., speckles) and subcompartments (e.g., nucleoli), this constitutes the first example of an ageing-specific effect on chromatin organization. With this proposal, we present preliminary evidence that CTCF clusters are indeed condensates that nucleate in close proximity to speckles and only upon senescence, and we go on to propose a combination of biochemical, functional and genomics assays, complemented by in silico modelling, to mechanistically dissect their emergence. We also hypothesize that these senescence-induced CTCF clusters (SICCs) form to shield particular loci from excessive DNA damage, and propose work to test this hypothesis. In the end, we anticipate obtain a molecular understanding of how senescence repurposes the cellular machinery and phase separation forces to rewire the human genome. This project aligns well with the SPP2191 priorities and will benefit from interactions with this emerging research community in Germany.

人类细胞复制潜力的耗尽标志着它们进入一种不可逆转的细胞周期停滞状态，即衰老。进入衰老阶段，细胞保持代谢活跃，也伴随着基因表达和 3D 染色质结构的巨大变化。这些变化中最显着的是 CTCF（3D 染色质结构域的关键组织者）聚集成大的衰老诱导的凝聚物。尽管相分离型力现在与核体（例如斑点）和子区室（例如核仁）的形成有关，但这构成了对染色质组织的衰老特异性影响的第一个例子。通过这一提议，我们提出了初步证据，证明 CTCF 簇确实是在靠近斑点且仅在衰老时才成核的凝聚体，并且我们继续提出生化、功能和基因组学测定的组合，并辅以计算机模拟，以机械地剖析它们的出现。我们还假设这些衰老诱导的 CTCF 簇 (SICC) 的形成是为了保护特定位点免受过度的 DNA 损伤，并提出了检验这一假设的工作。最后，我们期望获得对衰老如何重新利用细胞机制和相分离力来重新连接人类基因组的分子理解。该项目与 SPP2191 的优先事项非常一致，并将受益于与德国这个新兴研究界的互动。