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

Wilfried Engl, Aliz Kunstar-Thomas, Siyi Chen, Woei Shyuan Ng, Hendrik Sielaff and Ziqing Winston Zhao ()
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Wilfried Engl: National University of Singapore
Aliz Kunstar-Thomas: National University of Singapore
Siyi Chen: National University of Singapore
Woei Shyuan Ng: National University of Singapore
Hendrik Sielaff: National University of Singapore
Ziqing Winston Zhao: National University of Singapore

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52040-y

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