Acute BAF perturbation causes immediate changes in chromatin accessibility

Abstract

Cancer-associated loss-of-function mutations in genes coding for subunits of the BRG1/BRM associated factor (BAF) chromatin remodeling complexes ^{1– 8} often cause drastic chromatin accessibility changes, especially in important regulatory regions ^{9– 19} . However, it remains unknown how these changes are established over time (e.g. immediate consequences or long-term adaptations), and whether they are causative for intra-complex synthetic lethalities abrogating the formation or activity of BAF complexes ^{9, 20– 24} . Here, we use the dTAG system to induce acute degradation of BAF subunits and show that chromatin alterations are established faster than the duration of one cell cycle. Using a pharmacological inhibitor and a chemical degrader of the BAF complex ATPase subunits ^{25, 26} , we show that maintaining genome accessibility requires constant ATP-dependent remodeling. Completely abolishing BAF complex function by acute degradation of a synthetic lethal subunit in a paralog-deficient background results in a near-complete loss of chromatin accessibility at BAF-controlled sites, especially at super-enhancers, providing a mechanism for intra-complex synthetic lethalities.