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Diabetes. 2014 Jun;63(6):2148-57. doi: 10.2337/db13-1702. Epub 2014 Feb 11.

Linking the circadian rhythm gene Arntl2 to interleukin 21 expression in type 1 diabetes.

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  • 1Department of Developmental & Stem Cells Biology, Institut Pasteur, CNRS URA 2578, Laboratoire de Génétique Moléculaire Murine, Paris, FranceUniversité Pierre et Marie Curie, Cellule Pasteur UPMC, Paris, France.
  • 2Department of Developmental & Stem Cells Biology, Institut Pasteur, CNRS URA 2578, Laboratoire de Génétique Moléculaire Murine, Paris, France.
  • 3Department of Developmental & Stem Cells Biology, Institut Pasteur, CNRS URA 2578, Laboratoire de Génétique Moléculaire Murine, Paris, France ute-christine.rogner@pasteur.fr.

Abstract

The circadian rhythm-related aryl hydrocarbon receptor nuclear translocator-like 2 (Arntl2) gene has been identified as a candidate gene for the murine type 1 diabetes locus Idd6.3. Previous studies suggested a role in expansion of CD4(+)CD25(-) T cells, and this then creates an imbalance in the ratio between T-effector and CD4(+)CD25(+) T-regulator cells. Our transcriptome analyses identify the interleukin 21 (IL21) gene (Il21) as a direct target of ARNTL2. ARNTL2 binds in an allele-specific manner to the RNA polymerase binding site of the Il21 promoter and inhibits its expression in NOD.C3H congenic mice carrying C3H alleles at Idd6.3. IL21 is known to promote T-cell expansion, and in agreement with these findings, mice with C3H alleles at Idd6.3 produce lower numbers of CD4(+)IL21(+) and CD4(+) and CD8(+) T cells compared with mice with NOD alleles at Idd6.3. Our results describe a novel and rather unexpected role for Arntl2 in the immune system that lies outside of its predicted function in circadian rhythm regulation.

© 2014 by the American Diabetes Association.

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