Senescent cells cluster CTCF on nuclear speckles to instruct an alternative splicing program

Area of Science:

• Cellular Biology
• Genomics
• Molecular Biology

Background:

• Cellular senescence is a crucial process ending a cell's replicative lifespan.
• Senescence involves significant molecular changes, including the formation of senescence-induced clusters (SICCs) of CTCF.
• The mechanisms and functions of SICCs are not well understood.

Purpose of the Study:

• To investigate the molecular drivers behind the formation of senescence-induced clusters (SICCs).
• To understand the genomic consequences and functional significance of SICC formation.
• To elucidate how SICCs contribute to the commitment to cellular senescence.

Main Methods:

• Utilized 3D genomics, super-resolution imaging, and DNA tracing.
• Employed functional assays and computational modeling.
• Investigated the roles of SRRM2 and BANF1 in CTCF clustering and genome organization.

Main Results:

• SRRM2 and BANF1 are repurposed to cluster CTCF and alter genome architecture upon senescence entry.
• CTCF reorganization, relative to nuclear speckles, is essential for the senescence splicing program.
• Disrupting SICCs reverses alternative splicing patterns and postpones senescence.

Conclusions:

• Human cells utilize changes in nuclear biochemistry to alter genome architecture, directing splicing choices for senescence.
• SRRM2 and BANF1 play key roles in forming SICCs and driving the senescence fate.
• SICCs represent a critical mechanism linking nuclear organization to cell fate decisions in senescence.