Csf2 and Ptgs2 Epigenetic Dysregulation in Diabetes-prone Bicongenic B6.NODC11bxC1tb Mice

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

doi:10.4137/GEG.S29696

Csf2 and Ptgs2 Epigenetic Dysregulation in Diabetes-prone Bicongenic B6.NODC11bxC1tb Mice

Genet Epigenet. 2015 Oct 11:7:5-17. doi: 10.4137/GEG.S29696. eCollection 2015.

Authors

Erin Garrigan¹, Nicole S Belkin¹, Federica Seydel¹, Zhao Han¹, Jamal Carter¹, Marcia McDuffie², Laurence Morel¹, Ammon B Peck¹, Michael J Clare-Salzler¹, Mark Atkinson¹, Clive Wasserfall¹, Abdoreza Davoodi-Semiromi¹, Jing-da Shi¹, Carrie Haskell-Luevano¹, Li-Jun Yang¹, John J Alexander¹, Autumn Cdebaca¹, Teresa Piliant³, Corin Riggs⁴, Matthew Amick⁵, Sally A Litherland⁶

Affiliations

¹ Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
² School of Medicine, University of Virginia, Charlottesville, VA, USA.
³ Bionetics Corporation, Kennedy Space Center, FL, USA.
⁴ Bionetics Corporation, Kennedy Space Center, FL, USA. ; Sanford-Burnham Medical Research Institute, Diabetes and Obesity Center, Lake Nona-Orlando, FL, USA.
⁵ Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA. ; Sanford-Burnham Medical Research Institute, Diabetes and Obesity Center, Lake Nona-Orlando, FL, USA.
⁶ Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA. ; Sanford-Burnham Medical Research Institute, Diabetes and Obesity Center, Lake Nona-Orlando, FL, USA. ; Florida Hospital Cancer Institute, Orlando, FL, USA.

Abstract

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.

Keywords: autoimmune; congenic mice; cytokine; diabetes; epigenetic gene regulation; inflammation.

Abstract

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