Dissecting the principles guiding CTCF condensate formation in cellular ageing

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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.