AI Article Synopsis
- The study examines how STAT5, a signaling protein, misbinds to genes involved in inflammation in monocytes from Type 1 diabetic humans.
- Researchers used genetically modified mice (B6.NOD C11bxC1tb) to model these changes, demonstrating that specific genetic regions combined with STAT5 binding lead to altered expression of inflammatory genes CSF2 and PTGS2.
- These modified mice showed symptoms of diabetes, such as high blood sugar and pancreatic damage, suggesting that the gene expression changes in immune cells may increase diabetes risk even in mice that are not typically prone to autoimmune diseases.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603573 | PMC |
| http://dx.doi.org/10.4137/GEG.S29696 | DOI Listing |
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