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. 2025 Jan;32(1):125-136.
doi: 10.1038/s41594-024-01385-5. Epub 2024 Oct 4.

Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells

Affiliations

Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells

Zuhui Wang et al. Nat Struct Mol Biol. 2025 Jan.

Abstract

Pioneer transcription factors (PTFs) possess the unique capability to access closed chromatin regions and initiate cell fate changes, yet the underlying mechanisms remain elusive. Here, we characterized the single-molecule dynamics of PTFs targeting chromatin in living cells, revealing a notable 'confined target search' mechanism. PTFs such as FOXA1, FOXA2, SOX2, OCT4 and KLF4 sampled chromatin more frequently than non-PTF MYC, alternating between fast free diffusion in the nucleus and slower confined diffusion within mesoscale zones. Super-resolved microscopy showed closed chromatin organized as mesoscale nucleosome-dense domains, confining FOXA2 diffusion locally and enriching its binding. We pinpointed specific histone-interacting disordered regions, distinct from DNA-binding domains, crucial for confined target search kinetics and pioneer activity within closed chromatin. Fusion to other factors enhanced pioneer activity. Kinetic simulations suggested that transient confinement could increase target association rate by shortening search time and binding repeatedly. Our findings illuminate how PTFs recognize and exploit closed chromatin organization to access targets, revealing a pivotal aspect of gene regulation.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

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