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Acute BAF perturbation causes immediate changes in chromatin accessibility.

Sandra Schick1,2,3, Sarah Grosche4, Katharina Eva Kohl4,5

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Cancer-associated mutations in BRG1/BRM-associated factor (BAF) complexes alter chromatin rapidly. Constant ATP-dependent remodeling is crucial for maintaining genome accessibility, and loss of BAF function causes significant chromatin accessibility loss.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Loss-of-function mutations in BRG1/BRM-associated factor (BAF) chromatin-remodeling complexes are common in cancer.
  • These mutations lead to significant changes in chromatin accessibility, particularly in regulatory regions.
  • The temporal dynamics and causative role of these chromatin changes in synthetic lethality remain unclear.

Purpose of the Study:

  • To investigate the temporal dynamics of chromatin accessibility changes following acute BAF subunit loss.
  • To determine if constant ATP-dependent remodeling is required for maintaining genome accessibility.
  • To elucidate the mechanism by which BAF complex dysfunction leads to intracomplex synthetic lethality.

Main Methods:

  • Utilized the dTAG system for acute degradation of BAF subunits.
  • Employed a pharmacological inhibitor and chemical degrader targeting BAF complex ATPase subunits.
  • Assessed chromatin accessibility at BAF-controlled sites and superenhancers.

Main Results:

  • Chromatin alterations were established faster than one cell cycle after BAF subunit degradation.
  • Maintaining genome accessibility necessitates continuous ATP-dependent chromatin remodeling.
  • Complete BAF complex functional loss led to near-complete loss of chromatin accessibility at BAF-controlled sites and superenhancers.

Conclusions:

  • Acute loss of BAF subunits rapidly alters chromatin accessibility.
  • ATP-dependent remodeling is essential for sustained genome accessibility.
  • BAF complex dysfunction contributes to intracomplex synthetic lethality through profound chromatin accessibility loss.