DNA binding by FOXP3 domain-swapped dimer suggests mechanisms of long-range chromosomal interactions

Journal Article · Wed Jan 07 04:00:00 EST 2015 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gku1373· OSTI ID:1337190

Chen, Y.; Chen, C.; Zhang, Z.; Liu, C. -C.; Johnson, M. E.; Espinoza, C. A.; Edsall, L. E.; Ren, B.; Zhou, X. J.; Grant, S. F. A.; Wells, A. D.; Chen, L.

FOXP3 is a lineage-specific transcription factor that is required for regulatory T cell development and function. In this study, we determined the crystal structure of the FOXP3 forkhead domain bound to DNA. The structure reveals that FOXP3 can form a stable domain-swapped dimer to bridge DNA in the absence of cofactors, suggesting that FOXP3 may play a role in long-range gene interactions. To test this hypothesis, we used circular chromosome conformation capture coupled with high throughput sequencing (4C-seq) to analyze FOXP3-dependent genomic contacts around a known FOXP3-bound locus, Ptpn22. Our studies reveal that FOXP3 induces significant changes in the chromatin contacts between the Ptpn22 locus and other Foxp3-regulated genes, reflecting a mechanism by which FOXP3 reorganizes the genome architecture to coordinate the expression of its target genes. Our results suggest that FOXP3 mediates long-range chromatin interactions as part of its mechanisms to regulate specific gene expression in regulatory T cells.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE; NIH
• OSTI ID: 1337190
• Journal Information: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 2 Vol. 43; ISSN 0305-1048
• Publisher: Oxford University Press
• Country of Publication: United States
• Language: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES