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

Nature Structural & Molecular Biology volume 32, pages 125–136 (2025) Cite this article

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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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Fig. 1: PTFs sample chromatin frequently for targets by fast spaSMT.
The alternative text for this image may have been generated using AI.
Fig. 2: PTFs exhibit anisotropic diffusion and confined target search on chromatin.
The alternative text for this image may have been generated using AI.
Fig. 3: CTDFOXA2 is essential for FOXA2 anisotropic diffusion and target search.
The alternative text for this image may have been generated using AI.
Fig. 4: FOXA CTD enhances pioneering closed chromatin and is required for normal DE-specific gene expression.
The alternative text for this image may have been generated using AI.
Fig. 5: Two-color PALM reveals that FOXA2 targets compacted chromatin domains enriched for nucleosomes.
The alternative text for this image may have been generated using AI.
Fig. 6: Computer simulations reveal the kinetic advantage of confined target search.
The alternative text for this image may have been generated using AI.

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Data availability

All data needed to reproduce the results are available in the main text or Supplementary Information. Imaging data are available from Zenodo (https://doi.org/10.5281/zenodo.10427790). Genomic data were deposited to the National Center for Biotechnology Information’s Gene Expression Omnibus (accession number GSE203650). Source data are provided with this paper.

Code availability

The analysis code was deposited to GitHub (https://github.com/denglabpku/).

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Acknowledgements

We are grateful to R. Tjian, X. Darzacq and their laboratory members for assistance and discussions in initiating this study. We thank R. Salomon and G. Dailey for assistance in cell culture and cloning. We thank A. Amitai for providing computer code and discussion on kinetic simulation of target search. We thank P. Xu for sharing the mEosEM plasmid. We thank the National Center for Protein Sciences at Peking University for providing the FACS service and confocal microscopes. We thank the following for funding support: the National Key Research and Development Program of China (2020YFA0509502 to W.D.), the National Natural Science Foundation of China (32170566 to W.D.; T2225001 to H.G.), the Beijing Advanced Innovation Center for Genomics at Peking University (to W.D.) and the Peking-Tsinghua Center for Life Sciences (to W.D.).

Author information

Author notes

  1. These authors contributed equally: Zuhui Wang, Bo Wang, Di Niu.

Authors and Affiliations

  1. Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, China

    Zuhui Wang, Bo Wang, Di Niu, Chao Yin, Ying Bi, Hao Ge & Wulan Deng

  2. Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, Peking University, Beijing, China

    Zuhui Wang, Ying Bi & Wulan Deng

  3. Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China

    Zuhui Wang, Bo Wang, Di Niu, Chao Yin & Wulan Deng

  4. Peking-Tsinghua Center for Life Sciences (CLS), Peking University, Beijing, China

    Bo Wang, Di Niu, Chao Yin & Wulan Deng

  5. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA

    Claudia Cattoglio

  6. Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA

    Claudia Cattoglio

  7. Department of Developmental Biology, Stanford University, Stanford, CA, USA

    Kyle M. Loh

  8. Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA, USA

    Kyle M. Loh

  9. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA

    Luke D. Lavis

  10. Beijing International Center for Mathematical Research, Peking University, Beijing, China

    Hao Ge

  11. Beijing Advanced Innovation Center for Genomics (ICG), Peking University, Beijing, China

    Wulan Deng

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Contributions

Design of experiments, W.D., Z.W., B.W. and D.N. Live-cell SMT and analysis, Z.W. and W.D. ChIP-seq and ATAC-seq, D.N. RNA-seq, W.D. and C.C. Genomic analysis, B.W., D.N. and Y.B. Two-color PALM and analysis, B.W. Computer simulation of target search, H.G., Z.W. and B.W. Lentivirus production and MEF SMT, Y.C. hES cell culture and differentiation, W.D., Y.C. and K.M.L. Cell line construction, W.D., Z.W., D.N., B.W. and Y.B. Halo dye synthesis, L.D.L. Writing—original draft, W.D., Z.W., B.W. and D.N. Writing—review and editing, C.C., K.M.L. and H.G.

Corresponding author

Correspondence to Wulan Deng.

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Supplementary information

Supplementary Information (download PDF )

Supplementary Tables 1–5 and 7–10, Figs. 1–6 and unprocessed scans of blots present in the supplementary figures.

Reporting Summary (download PDF )

Peer Review File (download PDF )

Supplementary Table 6 (download XLSX )

RNA-seq expression level.

Supplementary Video 1 (download MP4 )

Fast spaSMT of indicated molecules was performed in the U2OS cells. The molecules were stained by 25 nM PA-JF646 and a 640-nm laser was used as the excitation light. The dataset corresponds to Fig. 1c, recorded with a time gap of 7.5 ms. For each frame, 1 ms of excitation laser was illuminated on the sample, followed by a pulse of 405-nm laser during the camera dead time (0.5 ms) to photoactivate a small portion of molecules. For the video, a ‘gray’ LUT was chosen.

Supplementary Video 2 (download MOV )

Time-lapsed phase-contrast and fluorescence images showing mitotic chromosome binding. The time stamp format is ‘hour:min’. The dataset corresponds to Supplementary Fig. 1h.

Supplementary Video 3 (download MP4 )

Representative of FOXA2-Halo trajectories showing confined diffusion in U2OS cells, recorded with a time gap of 7.5 ms. The yellow segments of the trajectories are the free segments classified by the HMM, whereas the blue segments are the bound segments. The semitransparent green dot shows the localized molecule position in each frame.

Supplementary Video 4 (download MP4 )

Representative slowSMT of endogenously tagged FOXA2-Halo in the DE cells using an exposure time of 500 ms. The white dashed line represents the boundary of the cell nucleus. The molecules were stained by 2.5 pM JF646 and a 640-nm laser was used as the excitation light. The molecule trajectories were color-coded; a 100-s video is shown.

Supplementary Video 5 (download MP4 )

Representative raw image sequence of endogenously tagged FOXA2-Halo in the DE cells from slowSMT.

Supplementary Video 6 (download MP4 )

The animation of the TF (black sphere) undergoing confined diffusion inside the monomers. Green spheres represent the monomers without CBS and orange spheres represent the monomers with CBS (purple sphere). The yellow lines following the TF represent the molecule trajectory.

Source data

Source Data Fig. 3 (download PDF )

Unprocessed western blots for Fig. 3b.

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Wang, Z., Wang, B., Niu, D. et al. Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells. Nat Struct Mol Biol 32, 125–136 (2025). https://doi.org/10.1038/s41594-024-01385-5

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