FOXP3 recognizes microsatellites and bridges DNA through multimerization
Open accessPublished version of a preprint
Abstract
FOXP3 is a transcription factor that is essential for the development of regulatory T cells, a branch of T cells that suppress excessive inflammation and autoimmunity 1–5 . However, the molecular mechanisms of FOXP3 remain unclear. Here we here show that FOXP3 uses the forkhead domain—a DNA-binding domain that is commonly thought to function as a monomer or dimer—to form a higher-order multimer after binding to T n G repeat microsatellites. The cryo-electron microscopy structure of FOXP3 in a complex with T 3 G repeats reveals a ladder-like architecture, whereby two double-stranded DNA molecules form the two ‘side rails’ bridged by five pairs of FOXP3 molecules, with each pair forming a ‘rung’. Each FOXP3 subunit occupies TGTTTGT within the repeats in a manner that is indistinguishable from that of FOXP3 bound to the forkhead consensus motif (TGTTTAC). Mutations in the intra-rung interface impair T n G repeat recognition, DNA bridging and the cellular functions of FOXP3, all without affecting binding to the forkhead consensus motif. FOXP3 can tolerate variable inter-rung spacings, explaining its broad specificity for T n G-repeat-like sequences in vivo and in vitro. Both FOXP3 orthologues and paralogues show similar T n G repeat recognition and DNA bridging. These findings therefore reveal a mode of DNA recognition that involves transcription factor homomultimerization and DNA bridging, and further implicates microsatellites in transcriptional regulation and diseases.
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Few studies have conclusively shown that TF multimerisation is a pre-requisite for efficient DNA-binding, but more recent works on BTB domain proteins and FOXP3 have suggested that higher-order assemblies of these TFs are needed for their cellular functions.
“Few studies have conclusively shown that TF multimerisation is a pre-requisite for efficient DNA-binding (e.g. SOX6 73 ), but more recent works on BTB domain proteins 74 and FOXP3 75 have suggested that higher-order assemblies of these TFs are needed for their cellular functions.”
From Tetramerisation governs SALL transcription factor function in development and disease (2025) · cites this paper as [75]
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Sorted by citations
Chen, X., Ghanizada, M., Mallajosyula, V. V. A., Solà, E., Capasso, R., Kathuria, K. R., & Davis, M. M. (2025) · Nature Immunology · doi:10.1038/s41590-024-02062-x · Cited by 57 · see citing works
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“The main function of Tregs is to suppress various immune responses, and Foxp3 is a key Treg transcription factor [39].”
BackgroundDynamic Foxp3–chromatin interaction controls tunable Treg cell function
He, M.-H., Zong, X., Xu, B., Qi, W., Huang, W., Djekidel, M. N., Zhang, Y., Pagala, V., Li, J., Hao, X., et al. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20232068 · Cited by 37 · see citing works
Light Triggered “Bacterial Bomb” to Amplify Tumor Pyroptosis
Liu, Y., Zeng, T., Bai, S.-Y., Fang, X., Cao, X.-P., Li, S.-Q., Chen, Q., Lu, C.-H., & Yang, H.-H. (2025) · Advanced Functional Materials · doi:10.1002/adfm.202505784 · Cited by 13 · see citing works
Elusive modes of Foxp3 activity in versatile regulatory T cells
He, M.-H., & Feng, Y. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1533823 · Cited by 11 · see citing works
Extracellular vesicles as the drug delivery vehicle for gene-based therapy
Aquino, A. D., Rubinstein, A., Кудрявцев, И. В., Yakovlev, A. A., & Головкин, А. С. (2025) · Applied Physics Reviews · doi:10.1063/5.0255519 · Cited by 9 · see citing works
Regulation of 3 D genome organization during T cell activation
Wang, B., & Bian, Q. (2024) · FEBS Journal · doi:10.1111/febs.17211 · Cited by 7 · see citing works
“Moreover, a recent study shows that FOXP3, when bound to tandem T 3 G repeats, forms a ladder-like architecture consisting of five pairs of FOXP3 molecules [72], providing another conformation for reinforcing EPIs (Fig.”
Cellular atlases of the entire mouse brain
Tosches, M. A., & Lee, H. J. (2023) · Nature · doi:10.1038/d41586-023-03781-1 · Cited by 7 · see citing works
The history and promise of Treg cells
Benoist, C. O., Vignali, D. A. A., Flavell, R. A., & Mathis, D. J. (2025) · Immunity · doi:10.1016/j.immuni.2025.11.011 · Cited by 5 · see citing works
Self-citationUltrastable and versatile multimeric ensembles of FoxP3 on microsatellites
Leng, F., Merino‐Urteaga, R., Wang, X., Zhang, W., Ha, T., & Hur, S. (2025) · Molecular Cell · doi:10.1016/j.molcel.2025.03.005 · Cited by 4 · see citing works
“14 Next, we examined FoxP3’s capacity to bridge more than two DNA copies for T2G, T3G, and T4G repeats by monitoring the ability of the folded nunchucks to recruit separate, Cy7-labeled DNA sharing the same repeat sequence as the nunchuck (TnG Cy7 ; Figure 4D, left).”
Self-citationZouein, A., Lende-Dorn, B. A., Galloway, K. E., Ellis, T., & Ceroni, F. (2025) · Trends in Biotechnology · doi:10.1016/j.tibtech.2025.05.006 · Cited by 4
Murakami, R., Hayatsu, N., Miyao, T., Liu, Z., Kino, Y., Shibata, S., Kawagoe, S., Matsuda, M., Iizuka, Y., Sugishita, H., et al. (2026) · Immunity · doi:10.1016/j.immuni.2026.03.005 · Cited by 4 · see citing works
A Fkh1/2 binding site array in the WHI5 promoter drives sub-scaling transcription
Kim, J., Xie, S., Valenzuela, L. F., Xiao, J. Y., Lanz, M. C., Gao, X., Swaffer, M. P., Mitchell, C. E., Rubin, S. M., Schmoller, K. M., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117304 · Cited by 2 · see citing works
“40 In our model, the Fkh protein can both bind a target site on the genome and bind other Fkh proteins already bound to adjacent sites.”
Leng, F., Clark, R., Zhang, W., Viennet, T., Wang, C., Arthanari, H., Wang, X., & Hur, S. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116633 · Cited by 2 · see citing works
“The TnG-repeat motif in our previous report 17 was used as a query motif, 4 and a search was performed against the mouse (GRCm38) genome, FoxP3 ChIP peaks or OCRs.”
Self-citationDistal enhancers loop to proximal enhancers, not to promoters
Struhl, K. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00889-2 · Cited by 2 · see citing works
Novel fold and wing structure of Forkhead transcription factor facilitate DNA binding
Wang, G., Jiang, Y.-B., Sun, Y.-Y., Nasertorabi, F., Weller, J. A., Mitra, R., Batyuk, A., Aparicio, O., Cherezov, V., & Rohs, R. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf946 · Cited by 1 · see citing works
“In some cases, such as FOXP3 [ 53 , 54 ], this bridging effect can be formed via a domain swap, whereby structural elements are exchanged with adjacent subunits, creating an intertwined multimer structure.”
Tetramerisation governs SALL transcription factor function in development and disease
Giuliani, S., Chhatbar, K., Wear, M., Guy, J., Mathieson, T., Burdett, H., George, L., Alston, G., Spanos, C., McHugh, T., et al. (2025) · bioRxiv · doi:10.1101/2025.10.27.684836
Targeting the FOXP3–T-bet interaction to restore Treg stability in IFN-γ–driven autoimmunity
Zhang, W., Liu, X., Gu, Z., Xu, J., Bao, Z., Liang, R., Xu, Z., Teng, D., Qu, G., Huang, Q., et al. (2026) · Cellular and Molecular Immunology · doi:10.1038/s41423-026-01468-x
“Protein puri fi cation was subsequently performed as previously described [31, 34].”
Self-citationBotchkova, E., Churov, A. V., & Arbatskiy, M. S. (2026) · Immuno · doi:10.3390/immuno6030049
“Dynamic chromatin interactions can alter function without proportional changes in total protein abundance [24,60].”
InfluentialJiang, X., & Zhang, W.-X. (2026) · STAR Protocols · doi:10.1016/j.xpro.2026.104513
Self-citationMultimerizing transcription factors FOXP3 and AIRE as chromatin architectural regulators
Leng, F., Huoh, Y., & Hur, S. (2026) · Nature Immunology · doi:10.1038/s41590-026-02483-w
Self-citationShamsi, A., Taghadosi, M., & khoobbakht, F. (2026) · Scandinavian Journal of Immunology · doi:10.1111/sji.70086
Feng, B.-J., Kohlmann, W. K., Nix, D. A., Atkinson, A., Boucher, K. M., Carroll, C., Stubben, C. J., Kolesar, J., Singer, E. A., Riedlinger, G., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-010417
“The authors gratefully acknowledge the Chan Soon Shiong Family Foundation for providing the funds for sequencing the Heritage 1000 Projects samples.”
- Authors
- Zhang, W., Leng, F., Wang, X., Ramirez, R. N., Park, J., Benoist, C., & Hur, S.
- Affiliations
- Boston Children's Hospital (US)
- Harvard University (US)
- Corresponding author
- Hur, Sun
- ORCID
- Venue
- Nature
- Published
- 2023-11-29
- Volume
- 624
- Issue
- 7991
- Pages
- 433-441
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC10719092
- OpenAlex
- W4389132725
- Cited by
- 42
- References
- 61
- Citations by year
- 2026: 13 · 2025: 19 · 2024: 7 · 2023: 3
- FWCI
- 3.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (1r01ai180137-01)
- National Institute of Allergy and Infectious Diseases (R01AI154653, R01AI111784, R01 AI180137, R01AI165697)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- Foxp3, forkhead domain, DNA recognition, DNA bridging, regulatory T cells, transcriptional regulation, protein-DNA complex structure
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