Persistent STAT5 phosphorylation and epigenetic dysregulation of GM-CSF and PGS2/COX2 expression in Type 1 diabetic human monocytes.

Autor: Erin Garrigan, Nicole S Belkin, John J Alexander, Zhao Han, Federica Seydel, Jamal Carter, Mark Atkinson, Clive Wasserfall, Michael J Clare-Salzler, Matthew A Amick, Sally A Litherland
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Zdroj: PLoS ONE, Vol 8, Iss 10, p e76919 (2013)
Druh dokumentu: article
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0076919
Popis: STAT5 proteins are adaptor proteins for histone acetylation enzymes. Histone acetylation at promoter and enhancer chromosomal regions opens the chromatin and allows access of transcription enzymes to specific genes in rapid response cell signals, such as in inflammation. Histone acetylation-mediated gene regulation is involved in expression of 2 key inflammatory response genes: CSF2, encoding granulocyte-macrophage colony stimulating factor (GM-CSF), and PTGS2, encoding prostaglandin synthase 2/cyclooxygenase 2 (PGS2/COX2). Prolonged CSF2 expression, high GM-CSF production, and GM-CSF activation of PTGS2 gene expression all are seen in type 1 diabetes (T1D) monocytes. Persistent phosphorylation activation of monocyte STAT5 (STAT5Ptyr) is also found in individuals with or at-risk for T1D. To examine whether elevated T1D monocyte STAT5Ptyr may be associated with aberrant inflammatory gene expression in T1D, blood monocytes from non-autoimmune controls and T1D patients were analyzed by flow cytometry for STAT5Ptyr activation, and by chromatin immuno-precipitation (ChIP) analyses for STAT5Ptyr's ability to bind at CSF2 and PTGS2 regulatory sites in association with histone acetylation. In unstimulated monocytes, STAT5Ptyr was elevated in 59.65% of T1D, but only 2.44% of control subjects (p
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