title: Csf2 and Ptgs2 Epigenetic Dysregulation in Diabetes-prone Bicongenic B6.NODC11bxC1tb Mice.
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.
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Garrigan
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Belkin
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Federica
authors.initials: F
authors.lastname: Seydel
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Han
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Jamal
authors.initials: J
authors.lastname: Carter
authors.affiliation: School of Medicine, University of Virginia, Charlottesville, VA, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: McDuffie
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Morel
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Ammon B
authors.initials: AB
authors.lastname: Peck
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clare-Salzler
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Atkinson
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Clive
authors.initials: C
authors.lastname: Wasserfall
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Abdoreza
authors.initials: A
authors.lastname: Davoodi-Semiromi
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Jing-da
authors.initials: JD
authors.lastname: Shi
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Haskell-Luevano
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Yang
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Alexander
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Autumn
authors.initials: A
authors.lastname: Cdebaca
authors.affiliation: Bionetics Corporation, Kennedy Space Center, FL, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Piliant
authors.affiliation: Bionetics Corporation, Kennedy Space Center, FL, USA. ; Sanford-Burnham Medical Research Institute, Diabetes and Obesity Center, Lake Nona-Orlando, FL, USA.
authors.forename: Corin
authors.initials: C
authors.lastname: Riggs
authors.affiliation: 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.
authors.forename: Matthew
authors.initials: M
authors.lastname: Amick
authors.affiliation: 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.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Litherland
keywords: autoimmune; congenic mice; cytokine; diabetes; epigenetic gene regulation; inflammation