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bioRxiv · 10.1101/2025.09.16.676304

FoxP3 forms a head-to-head dimer in vivo and stabilizes its multimerization on adjacent microsatellites

Leng, F.·Clark, R.·Zhang, W.·Viennet, T.·Arthanari, H.·Wang, X.·Hur, s.
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Abstract

FoxP3, the master regulator of Tregs, employs two DNA-binding modes to recognize diverse DNA sequences. It multimerizes on long TnG repeats (n = 2-5) to bridge DNA segments and stabilize chromatin loops, and it forms head-to-head (H-H) dimers on inverted repeat forkhead motifs (IR-FKHM) without bridging DNA. Although genomic data confirm its multimeric role, in vivo evidence for H-H dimerization has been elusive. Here, unbiased pull-down sequencing uncovers a range of relaxed motifs that drive H-H dimerization, enabling systematic genome- wide analysis. We demonstrate that FoxP3 binds genomic DNA as both H-H dimers and multimers in Tregs, with H-H binding often seeding and stabilizing multimerization on adjacent TnG repeats--especially on shorter, suboptimal repeats. While multimerization is conserved across FoxP family members, H-H dimerization is unique to FoxP3 orthologs, conferred by its divergent accessory loop. This dual-mode strategy broadens FoxP3s sequence repertoire and enhances its architectural function in chromatin looping.

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Leng, F., Clark, R., Zhang, W., Viennet, T., Arthanari, H., Wang, X., Hur, s.. 2025-09-18. FoxP3 forms a head-to-head dimer in vivo and stabilizes its multimerization on adjacent microsatellites. https://doi.org/10.1101/2025.09.16.676304

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