Persistent STAT5 Phosphorylation and Epigenetic Dysregulation of GM-CSF and PGS2/COX2 Expression in Type 1 Diabetic Human Monocytes

Erin Garrigan, Nicole S. Belkin, John J. Alexander, Zhao Han, Federica Seydel, Jamal H. Carter, Mark Atkinson, Clive Wasserfall, Michael J. Clare-Salzler, Matthew A. Amick, Sally A. Litherland

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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<0.0001). Increased STAT5Ptyr correlated with T1D disease duration (p = 0.0030, r2 = 0.0784). Unstimulated (p = 0.140) and GM-CSF-stimulated (p = 0.0485) T1D monocytes, had greater STAT5Ptyr binding to epigenetic regulatory sites upstream of CSF2 than control monocytes. Increased STAT5Ptyr binding in T1D monocytes was concurrent with binding at these sites of STAT6Ptyr (p = 0.0283), CBP/P300 histone acetylase, acetylated histones H3, SMRT/NCoR histone deacetylase (p = 0.0040), and RNA Polymerase II (p = 0.0040). Our study indicates that in T1D monocytes, STAT5Ptyr activation is significantly higher and that STAT5Ptyr is found bound to CSF2 promoter and PTGS2 enhancer regions coincident with histone acetylation and RNA polymerase II. These findings suggest that the persistent activation of STAT5 by GM-CSF may be involved in altering the epigenetic regulation of these inflammatory response genes in T1D monocytes.

Original languageEnglish (US)
Article numbere76919
JournalPLoS One
Volume8
Issue number10
DOIs
StatePublished - Oct 18 2013
Externally publishedYes

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granulocyte-macrophage colony-stimulating factor
Phosphorylation
insulin-dependent diabetes mellitus
prostaglandin synthase
Cyclooxygenase 2
Granulocyte-Macrophage Colony-Stimulating Factor
Prostaglandin-Endoperoxide Synthases
Medical problems
Type 1 Diabetes Mellitus
Epigenomics
epigenetics
monocytes
Monocytes
phosphorylation
Acetylation
histones
Histones
acetylation
Chemical activation
Gene expression

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Persistent STAT5 Phosphorylation and Epigenetic Dysregulation of GM-CSF and PGS2/COX2 Expression in Type 1 Diabetic Human Monocytes. / Garrigan, Erin; Belkin, Nicole S.; Alexander, John J.; Han, Zhao; Seydel, Federica; Carter, Jamal H.; Atkinson, Mark; Wasserfall, Clive; Clare-Salzler, Michael J.; Amick, Matthew A.; Litherland, Sally A.

In: PLoS One, Vol. 8, No. 10, e76919, 18.10.2013.

Research output: Contribution to journalArticle

Garrigan, E, Belkin, NS, Alexander, JJ, Han, Z, Seydel, F, Carter, JH, Atkinson, M, Wasserfall, C, Clare-Salzler, MJ, Amick, MA & Litherland, SA 2013, 'Persistent STAT5 Phosphorylation and Epigenetic Dysregulation of GM-CSF and PGS2/COX2 Expression in Type 1 Diabetic Human Monocytes', PLoS One, vol. 8, no. 10, e76919. https://doi.org/10.1371/journal.pone.0076919
Garrigan, Erin ; Belkin, Nicole S. ; Alexander, John J. ; Han, Zhao ; Seydel, Federica ; Carter, Jamal H. ; Atkinson, Mark ; Wasserfall, Clive ; Clare-Salzler, Michael J. ; Amick, Matthew A. ; Litherland, Sally A. / Persistent STAT5 Phosphorylation and Epigenetic Dysregulation of GM-CSF and PGS2/COX2 Expression in Type 1 Diabetic Human Monocytes. In: PLoS One. 2013 ; Vol. 8, No. 10.
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abstract = "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<0.0001). Increased STAT5Ptyr correlated with T1D disease duration (p = 0.0030, r2 = 0.0784). Unstimulated (p = 0.140) and GM-CSF-stimulated (p = 0.0485) T1D monocytes, had greater STAT5Ptyr binding to epigenetic regulatory sites upstream of CSF2 than control monocytes. Increased STAT5Ptyr binding in T1D monocytes was concurrent with binding at these sites of STAT6Ptyr (p = 0.0283), CBP/P300 histone acetylase, acetylated histones H3, SMRT/NCoR histone deacetylase (p = 0.0040), and RNA Polymerase II (p = 0.0040). Our study indicates that in T1D monocytes, STAT5Ptyr activation is significantly higher and that STAT5Ptyr is found bound to CSF2 promoter and PTGS2 enhancer regions coincident with histone acetylation and RNA polymerase II. These findings suggest that the persistent activation of STAT5 by GM-CSF may be involved in altering the epigenetic regulation of these inflammatory response genes in T1D monocytes.",
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AU - Alexander, John J.

AU - Han, Zhao

AU - Seydel, Federica

AU - Carter, Jamal H.

AU - Atkinson, Mark

AU - Wasserfall, Clive

AU - Clare-Salzler, Michael J.

AU - Amick, Matthew A.

AU - Litherland, Sally A.

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N2 - 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<0.0001). Increased STAT5Ptyr correlated with T1D disease duration (p = 0.0030, r2 = 0.0784). Unstimulated (p = 0.140) and GM-CSF-stimulated (p = 0.0485) T1D monocytes, had greater STAT5Ptyr binding to epigenetic regulatory sites upstream of CSF2 than control monocytes. Increased STAT5Ptyr binding in T1D monocytes was concurrent with binding at these sites of STAT6Ptyr (p = 0.0283), CBP/P300 histone acetylase, acetylated histones H3, SMRT/NCoR histone deacetylase (p = 0.0040), and RNA Polymerase II (p = 0.0040). Our study indicates that in T1D monocytes, STAT5Ptyr activation is significantly higher and that STAT5Ptyr is found bound to CSF2 promoter and PTGS2 enhancer regions coincident with histone acetylation and RNA polymerase II. These findings suggest that the persistent activation of STAT5 by GM-CSF may be involved in altering the epigenetic regulation of these inflammatory response genes in T1D monocytes.

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