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bioRxiv · 10.1101/2024.07.16.603680

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

Palikyras, S.·Varamogianni-Mamatsi, V.·Zhu, Y.·Ramasamy, S.·Mizi, A.·Liebermann, I.·Stavropoulou, A.·Papadionysiou, I.·Bartsch, D.·Kargapolova, Y.·Sofiadis, K.·Nikolaou, C.·Kurian, L.·Oudelaar, M.·Barbieri, M.·Papantonis, A.
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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. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/603680v1_ufig1.gif" ALT="Figure 1"> View larger version (85K): org.highwire.dtl.DTLVardef@cfb561org.highwire.dtl.DTLVardef@8cfdf3org.highwire.dtl.DTLVardef@7485d5org.highwire.dtl.DTLVardef@1fe9051_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIHMGB2-bound loci compete with CTCF-bound ones for nuclear speckle association C_LIO_LISenescent cells repurpose SRRM2 and BANF1 to cluster CTCF on speckles C_LIO_LIBANF1 is essential, but not sufficient for CTCF clustering C_LIO_LIThe SRRM2 RNA-binding domain directs CTCF clustering C_LIO_LISICCs rewire chromatin positioning to sustain the senescence splicing program C_LI

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Palikyras, S., Varamogianni-Mamatsi, V., Zhu, Y., Ramasamy, S., Mizi, A., Liebermann, I., Stavropoulou, A., Papadionysiou, I., Bartsch, D., Kargapolova, Y., Sofiadis, K., Nikolaou, C., Kurian, L., Oudelaar, M., Barbieri, M., Papantonis, A.. 2024-07-16. Senescent cells cluster CTCF on nuclear speckles to sustain their splicing program. https://doi.org/10.1101/2024.07.16.603680

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