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

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