Csf2 and Ptgs2 Epigenetic Dysregulation in Diabetesprone Bicongenic B6. NODC11bxC1tb Mice

Garrigan, Erin, Belkin, Nicole S., Seydel, Federica, Han, Zhao, Carter, Jamal, McDuffie, Marcia, Morel, Laurence, Peck, Ammon B., Clare-Salzler, Michael J., Atkinson, Mark, Wasserfall, Clive, Davoodi-Semiromi, Abdoreza, Shi, Jing-da, Haskell-Luevano, Carrie, Yang, Li-Jun, Alexander, John J., Cdebaca, Autumn, Piliant, Teresa, Riggs, Corin, Amick, Matthew, Litherland, Sally A.

This work was supported by grants to SAL from the NINIH/NINIDDK (DK002947 & DK08082) and the JDRF (33-2008-407) and to MAtkinson/MJCSCS from the NINIH/NINIAID (PO1 AI42288). The authors confirm that the funders had no influence over the study design, content of the article, or selection of this journal.

In Type 1 diabetic (T1D) human monocytes, STAT5 aberrantly binds to epigenetic regulatory sites of two proinflammatory genes, CSF2 (encoding granulocyte-macrophage colony-stimulating factor) and PTGS2 (encoding prostaglandin synthase 2/cyclooxygenase 2). Bicongenic B6. NOD C11bxC1tb mice re-create this phenotype of T1D monocytes with only two nonobese diabetic (NOD) Idd subloci (130.8 Mb-149.7 Mb, of Idd5 on Chr 1 and 32.08-53.85 Mb of Idd4.3 on Chr11) on C57BL/6 genetic background. These two Idd loci interact through STAT5 binding at upstream regulatory regions affecting Csf2 (Chr 11) and Ptgs2 (Chr 1) expression. B6. NODC11bxC1tb mice exhibited hyperglycemia and immune destruction of pancreatic islets between 8 and 30 weeks of age, with 12%-22% penetrance. Thus, B6. NODC11bxC1tb mice embody NOD epigenetic dysregulation of gene expression in myeloid cells, and this defect appears to be sufficient to impart genetic susceptibility to diabetes in an otherwise genetically nonautoimmune mouse.

Csf2 and Ptgs2 Epigenetic Dysregulation in Diabetesprone Bicongenic B6. NODC11bxC1tb Mice Article