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Mol Cell. 2014 Apr 10;54(1):56-66. doi: 10.1016/j.molcel.2014.02.004. Epub 2014 Mar 6.

Oct-1 regulates IL-17 expression by directing interchromosomal associations in conjunction with CTCF in T cells.

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
4
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
5
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
6
Department of Cell Biology and Genetics, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
7
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: richard.flavell@yale.edu.

Abstract

Interchromosomal associations can regulate gene expression, but little is known about the molecular basis of such associations. In response to antigen stimulation, naive T cells can differentiate into Th1, Th2, and Th17 cells expressing IFN-γ, IL-4, and IL-17, respectively. We previously reported that in naive T cells, the IFN-γ locus is associated with the Th2 cytokine locus. Here we show that the Th2 locus additionally associates with the IL-17 locus. This association requires a DNase I hypersensitive region (RHS6) at the Th2 locus. RHS6 and the IL-17 promoter both bear Oct-1 binding sites. Deletion of either of these sites or Oct-1 gene impairs the association. Oct-1 and CTCF bind their cognate sites cooperatively, and CTCF deficiency similarly impairs the association. Finally, defects in the association lead to enhanced IL-17 induction. Collectively, our data indicate Th17 lineage differentiation is restrained by the Th2 locus via interchromosomal associations organized by Oct-1 and CTCF.

PMID:
24613343
PMCID:
PMC4058095
DOI:
10.1016/j.molcel.2014.02.004
[Indexed for MEDLINE]
Free PMC Article

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