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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.

SUBMITTER: Chen Y 

PROVIDER: S-EPMC4333414 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Chen Yongheng Y   Chen Chunxia C   Zhang Zhe Z   Liu Chun-Chi CC   Johnson Matthew E ME   Espinoza Celso A CA   Edsall Lee E LE   Ren Bing B   Zhou Xianghong Jasmine XJ   Grant Struan F A SF   Wells Andrew D AD   Chen Lin L  

Nucleic acids research 20150107 2


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 seq  ...[more]

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