| Autor: |
Engl, Wilfried, Kunstar-Thomas, Aliz, Chen, Siyi, Ng, Woei Shyuan, Sielaff, Hendrik, Zhao, Ziqing Winston |
| Předmět: |
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| Zdroj: |
Nature Communications; 9/2/2024, Vol. 15 Issue 1, p1-15, 15p |
| Abstrakt: |
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. Live-cell single-molecule imaging of human SWI/SNF chromatin remodeler complex reveals nanoscale binding "hotspots" in cell nucleus, and uncovers multi-modal aberrations in DNA binding dynamics associated with mutants implicated in various cancers. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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