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Single-molecule imaging of SWI/SNF chromatin remodelers reveals bromodomain-mediated and cancer-mutants-specific landscape of multi-modal DNA-binding dynamics

Author

Listed:
  • Wilfried Engl

    (National University of Singapore
    National University of Singapore)

  • Aliz Kunstar-Thomas

    (National University of Singapore
    National University of Singapore)

  • Siyi Chen

    (National University of Singapore
    National University of Singapore)

  • Woei Shyuan Ng

    (National University of Singapore
    National University of Singapore)

  • Hendrik Sielaff

    (National University of Singapore
    National University of Singapore)

  • Ziqing Winston Zhao

    (National University of Singapore
    National University of Singapore
    National University of Singapore
    National University of Singapore)

Abstract

Despite their prevalent cancer implications, the in vivo dynamics of SWI/SNF chromatin remodelers and how misregulation of such dynamics underpins cancer remain poorly understood. Using live-cell single-molecule tracking, we quantify the intranuclear diffusion and chromatin-binding of three key subunits common to all major human SWI/SNF remodeler complexes (BAF57, BAF155 and BRG1), and resolve two temporally distinct stable binding modes for the fully assembled complex. Super-resolved density mapping reveals heterogeneous, nanoscale remodeler binding “hotspots” across the nucleoplasm where multiple binding events (especially longer-lived ones) preferentially cluster. Importantly, we uncover distinct roles of the bromodomain in modulating chromatin binding/targeting in a DNA-accessibility-dependent manner, pointing to a model where successive longer-lived binding within “hotspots” leads to sustained productive remodeling. Finally, systematic comparison of six common BRG1 mutants implicated in various cancers unveils alterations in chromatin-binding dynamics unique to each mutant, shedding insight into a multi-modal landscape regulating the spatio-temporal organizational dynamics of SWI/SNF remodelers.

Suggested Citation

  • Wilfried Engl & Aliz Kunstar-Thomas & Siyi Chen & Woei Shyuan Ng & Hendrik Sielaff & Ziqing Winston Zhao, 2024. "Single-molecule imaging of SWI/SNF chromatin remodelers reveals bromodomain-mediated and cancer-mutants-specific landscape of multi-modal DNA-binding dynamics," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52040-y
    DOI: 10.1038/s41467-024-52040-y
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