Csf2 and Ptgs2 Epigenetic Dysregulation in Diabetes-prone Bicongenic B6.NODC11bxC1tb Mice-Reference-Cited by-同舟云学术

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

Published:2015-01 Issue: Volume:7 Page:GEG.S29696
ISSN:1179-237X
Container-title:Genetics & Epigenetics
language:en
Short-container-title:Genet Epigenet

Author:

Garrigan Erin¹,Belkin Nicole S.¹,Seydel Federica¹,Han Zhao¹,Carter Jamal¹,McDuffie Marcia²,Morel Laurence¹,Peck Ammon B.¹,Clare-Salzler Michael J.¹,Atkinson Mark¹,Wasserfall Clive¹,Davoodi-Semiromi Abdoreza¹,Shi Jing-da³,Haskell-Luevano Carrie⁴,Yang Li-Jun¹,Alexander John J.¹,Cdebaca Autumn⁵,Piliant Teresa⁵,Riggs Corin⁵⁶,Amick Matthew¹⁶,Litherland Sally A.¹⁶⁷

Affiliation:

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. Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA.

4. Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.

5. Bionetics Corporation, Kennedy Space Center, FL, USA.

6. Sanford-Burnham Medical Research Institute, Diabetes and Obesity Center, Lake Nona-Orlando, FL, USA.

7. 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.

Publisher

SAGE Publications

Subject

Genetics,Biochemistry

Link

http://journals.sagepub.com/doi/pdf/10.4137/GEG.S29696

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