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

Abstract

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.

Authors:
; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1337190
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nucleic Acids Research; Journal Volume: 43; Journal Issue: 2
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

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., and Chen, L. DNA binding by FOXP3 domain-swapped dimer suggests mechanisms of long-range chromosomal interactions. United States: N. p., 2015. Web. doi:10.1093/nar/gku1373.
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. DNA binding by FOXP3 domain-swapped dimer suggests mechanisms of long-range chromosomal interactions. United States. doi:10.1093/nar/gku1373.
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., and Chen, L. Wed . "DNA binding by FOXP3 domain-swapped dimer suggests mechanisms of long-range chromosomal interactions". United States. doi:10.1093/nar/gku1373.
@article{osti_1337190,
title = {DNA binding by FOXP3 domain-swapped dimer suggests mechanisms of long-range chromosomal interactions},
author = {Chen, Y. and Chen, C. and Zhang, Z. and Liu, C. -C. and Johnson, M. E. and Espinoza, C. A. and Edsall, L. E. and Ren, B. and Zhou, X. J. and Grant, S. F. A. and Wells, A. D. and Chen, L.},
abstractNote = {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.},
doi = {10.1093/nar/gku1373},
journal = {Nucleic Acids Research},
number = 2,
volume = 43,
place = {United States},
year = {Wed Jan 07 00:00:00 EST 2015},
month = {Wed Jan 07 00:00:00 EST 2015}
}