Several cancer core regulatory circuitries (CRCs) depend on the sustained generation of DNA accessibility by SWI/SNF chromatin remodelers. However, the window when SWI/SNF is acutely essential in these settings has not been identified. Here we used neuroblastoma (NB) cells to model and dissect the relationship between cell-cycle progression and SWI/SNF ATPase activity. We find that SWI/SNF inactivation impairs coordinated occupancy of non-pioneer CRC members at enhancers within 1 hour, rapidly breaking their autoregulation. By precisely timing inhibitor treatment following synchronization, we show that SWI/SNF is dispensable for survival in S and G2/M, but becomes acutely essential only during G1 phase. We furthermore developed a new approach to analyze the oscillating patterns of genome-wide DNA accessibility across the cell cycle, which revealed that SWI/SNF-dependent CRC binding sites are enriched at enhancers with peak accessibility during G1 phase, where they activate genes involved in cell-cycle progression. SWI/SNF inhibition strongly impairs G1-S transition and potentiates the ability of retinoids used clinically to induce cell-cycle exit. Similar cell-cycle effects in diverse SWI/SNF-addicted settings highlight G1-S transition as a common cause of SWI/SNF dependency. Our results illustrate that deeper knowledge of the temporal patterns of enhancer-related dependencies may aid the rational targeting of addicted cancers.

Cancer cells driven by runaway transcription factor networks frequently depend on the cellular machinery that promotes DNA accessibility. For this reason, recently developed small molecules that impair SWI/SNF (or BAF) chromatin remodeling activity have been under active evaluation as anti-cancer agents. However, exactly when SWI/SNF activity is essential in dependent cancers has remained unknown. By combining live-cell imaging and genome-wide profiling in neuroblastoma cells, Cermakova et al. discover that SWI/SNF activity is needed for survival only during G1 phase of the cell cycle. The authors reveal that in several cancer settings, dependency on SWI/SNF arises from the need to reactivate factors involved in G1-S transition. Because of this role, authors find that SWI/SNF inhibition potentiates cell-cycle exit by retinoic acid.

Cancer and Cell Biology Graduate Program Baylor College of Medicine Houston TX USA

Dan L Duncan Comprehensive Cancer Center Baylor College of Medicine Houston TX USA

Department of Bioengineering Rice University Houston TX USA

Department of Bioinformatics and Computational Biology The University of Texas MD Anderson Cancer Center Houston TX USA

Department of Molecular and Cellular Biology and Center for Precision Environmental Health Baylor College of Medicine Houston TX USA

Department of Pediatrics Section of Hematology Oncology Texas Children's Cancer and Hematology Center Baylor College of Medicine Houston TX USA

Development Disease Models and Therapeutics Graduate Program Baylor College of Medicine Houston TX USA

Graduate Program in Quantitative and Computational Biosciences Baylor College of Medicine Houston TX USA

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague Czech Republic

Program in Developmental Biology Baylor College of Medicine Houston TX USA

Stem Cells and Regenerative Medicine Center Center for Cell and Gene Therapy and Department of Molecular and Cellular Biology Baylor College of Medicine Houston TX USA

Translational Biology and Molecular Medicine Graduate Program Houston TX USA

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