Csf2 and Ptgs2 epigenetic dysregulation in diabetesprone bicongenic B6.NODC11bxC1tb mice

Erin Garrigan, Nicole S. Belkin, Federica Seydel, Zhao Han, Jamal H. 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 AmickSally A. Litherland, R. Bober

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5-17
Number of pages13
JournalGenetics and Epigenetics
Volume1
Issue number7
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Keywords

  • Autoimmune
  • Congenic mice
  • Cytokine
  • Diabetes
  • Epigenetic gene regulation
  • Inflammation

ASJC Scopus subject areas

  • Biochemistry
  • Genetics

Cite this

Garrigan, E., Belkin, N. S., Seydel, F., Han, Z., Carter, J. H., McDuffie, M., Morel, L., Peck, A. B., Clare-Salzler, M. J., Atkinson, M., Wasserfall, C., Davoodi-Semiromi, A., Shi, J. D., Haskell-Luevano, C., Yang, L. J., Alexander, J. J., Cdebaca, A., Piliant, T., Riggs, C., ... Bober, R. (2015). Csf2 and Ptgs2 epigenetic dysregulation in diabetesprone bicongenic B6.NODC11bxC1tb mice. Genetics and Epigenetics, 1(7), 5-17. https://doi.org/10.4137/GEG.S29696