Imbalance between HDAC and HAT activities drives aberrant STAT1/MyD88 expression in macrophages from type 1 diabetic mice.

Filgueiras LR, Brandt SL, Ramalho TR, Jancar S, Serezani CH
J Diabetes Complications. 2017 31 (2): 334-339

PMID: 27623388 · PMCID: PMC5296405 · DOI:10.1016/j.jdiacomp.2016.08.001

AIMS - To investigate the hypothesis that alteration in histone acetylation/deacetylation triggers aberrant STAT1/MyD88 expression in macrophages from diabetics. Increased STAT1/MyD88 expression is correlated with sterile inflammation in type 1 diabetic (T1D) mice.

METHODS - To induce diabetes, we injected low-doses of streptozotocin in C57BL/6 mice. Peritoneal or bone marrow-differentiated macrophages were cultured in 5mM (low) or 25mM (high glucose). ChIP analysis of macrophages from nondiabetic or diabetic mice was performed to determine acetylation of lysine 9 in histone H3 in MyD88 and STAT1 promoter regions. Macrophages from diabetic mice were treated with the histone acetyltransferase inhibitor anacardic acid (AA), followed by determination of mRNA expression by qPCR.

RESULTS - Increased STAT1 and MyD88 expression in macrophages from diabetic but not naive mice cultured in low glucose persisted for up to 6days. Macrophages from diabetic mice exhibited increased activity of histone acetyltransferases (HAT) and decreased histone deacetylases (HDAC) activity. We detected increased H3K9Ac binding to Stat1/Myd88 promoters in macrophages from T1D mice and AA in vitro treatment reduced STAT1 and MyD88 mRNA expression.

CONCLUSIONS/INTERPRETATION - These results indicate that histone acetylation drives elevated Stat1/Myd88 expression in macrophages from diabetic mice, and this mechanism may be involved in sterile inflammation and diabetes comorbidities.

Copyright © 2016 Elsevier Inc. All rights reserved.

MeSH Terms (22)

Acetylation Animals Bone Marrow Cells Cells, Cultured Diabetes Mellitus, Type 1 Enzyme Inhibitors Epigenesis, Genetic Gene Expression Regulation Glucose Histone Acetyltransferases Histone Deacetylases Histones Macrophages Macrophages, Peritoneal Male Mice, Inbred C57BL Myeloid Differentiation Factor 88 Osmolar Concentration Promoter Regions, Genetic Protein Processing, Post-Translational STAT1 Transcription Factor Streptozocin

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