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Senescent cells cluster CTCF on nuclear speckles to sustain their splicing program [APEX-seq]

ABSTRACT: Senescence —the endpoint of replicative lifespan for normal cells— is established via a complex sequence of molecular events. One such event is the dramatic reorganization of CTCF into senescence-induced clusters (SICCs). However, the molecular determinants, genomic consequences, and functional purpose of SICCs remained unknown. Here, we combine functional assays, super-resolution imaging, and 3D genomics with computational modelling to dissect SICC emergence. We establish that the competition between CTCF-bound and non-bound loci dictates clustering propensity. Upon senescence entry, cells repurpose SRRM2 —a key component of nuclear speckles— and BANF1 —a ‘molecular glue’ for chromosomes— to cluster CTCF and rewire genome architecture. This CTCF-centric reorganization in reference to nuclear speckles functionally sustains the senescence splicing program, as SICC disruption fully reverts alternative splicing patterns. We therefore uncover a new paradigm, whereby cells translate changes in nuclear biochemistry into architectural changes directing splicing choices so as to commit to the fate of senescence.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283687 | GEO | 2024/12/12

REPOSITORIES: GEO

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Senescent cells cluster CTCF on nuclear speckles to sustain their splicing program [Chipmentation]

Project description:Senescence —the end-point of the replicative life span of normal cells— is characterized by a complex sequence of molecular and biochemical events. One of these is the dramatic reorganization of CTCF into large senescence-induced CTCF clusters (SICCs). However, the molecular determinants, genomic consequences, and functional purpose of SICCs remained unknown. Here, we combine super-resolution imaging, 3D genomics, and functional assays with computational modelling to address all aspects of SICC emergence. First, we used modelling and data from the overexpression of nuclear factors lost upon senescence entry to explain how changes in the nuclear environment allow for CTCF clustering. Second, we discovered that cells entering senescence repurpose SRRM2 —a key component of nuclear speckles— and BANF1 —a protein known to act as ‘molecular glue’ for chromosomes during mitosis— to cluster CTCF on the surface of speckles, while rewiring higher-order genome architecture. Last, we could show that SICCs are required for the faithful execution of the senescence splicing program as their disruption by SRRM2 or BANF1 depletion reverts splicing choices. Together, the senescence-specific clustering of CTCF on nuclear speckles is a new paradigm of a change in the biochemical environment of the nucleus being translated into its architectural reorganization to allow for the deployment of a splicing program driving homeostatic deregulation.

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