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<a href="http://doi.org/10.1074/jbc.M113.512269" target="_blank" rel="noreferrer noopener">http://doi.org/10.1074/jbc.M113.512269</a>
Pages
6877–6885
Issue
10
Volume
289
Dublin Core
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Title
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Modulation of ten-eleven translocation 1 (TET1), Isocitrate Dehydrogenase (IDH) expression, alpha-Ketoglutarate (alpha-KG), and DNA hydroxymethylation levels by interleukin-1beta in primary human chondrocytes.
Publisher
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The Journal of biological chemistry
Date
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2014
2014-03
Subject
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*DNA Methylation; *Epigenesis; 5-hmC; 5-Methylcytosine/analogs & derivatives; Chondrocytes; Chondrocytes/chemistry/*metabolism; Cytokine; Cytosine/*analogs & derivatives/analysis/metabolism; Dioxygenase; DNA Methylation; DNA-Binding Proteins/*biosynthesis/genetics; Epigenetics; Genetic; Humans; IL-1; Interleukin-1beta/pharmacology/*physiology; Isocitrate Dehydrogenase/*biosynthesis/genetics; Ketoglutaric Acids/*metabolism; Messenger/biosynthesis/genetics; Mixed Function Oxygenases; Primary Cell Culture; Proto-Oncogene Proteins/*biosynthesis/genetics; RNA; TNF-alpha; Tumor Necrosis Factor-alpha/pharmacology/physiology
Creator
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Haseeb Abdul; Makki Mohammad Shahidul; Haqqi Tariq M
Description
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5-Hydroxymethylcytosine (5-hmC) generated by ten-eleven translocation 1-3 (TET1-3) enzymes is an epigenetic mark present in many tissues with different degrees of abundance. IL-1beta and TNF-alpha are the two major cytokines present in arthritic joints that modulate the expression of many genes associated with cartilage degradation in osteoarthritis. In the present study, we investigated the global 5-hmC content, the effects of IL-1beta and TNF-alpha on 5-hmC content, and the expression and activity of TETs and isocitrate dehydrogenases in primary human chondrocytes. The global 5-hmC content was found to be approximately 0.1% of the total genome. There was a significant decrease in the levels of 5-hmC and the TET enzyme activity upon treatment of chondrocytes with IL-1beta alone or in combination with TNF-alpha. We observed a dramatic (10-20-fold) decrease in the levels of TET1 mRNA expression and a small increase (2-3-fold) in TET3 expression in chondrocytes stimulated with IL-1beta and TNF-alpha. IL-1beta and TNF-alpha significantly suppressed the activity and expression of IDHs, which correlated with the reduced alpha-ketoglutarate levels. Whole genome profiling showed an erasure effect of IL-1beta and TNF-alpha, resulting in a significant decrease in hydroxymethylation in a myriad of genes including many genes that are important in chondrocyte physiology. Our data demonstrate that DNA hydroxymethylation is modulated by pro-inflammatory cytokines via suppression of the cytosine hydroxymethylation machinery. These data point to new mechanisms of epigenetic control of gene expression by pro-inflammatory cytokines in human chondrocytes.
Identifier
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<a href="http://doi.org/10.1074/jbc.M113.512269" target="_blank" rel="noreferrer noopener">10.1074/jbc.M113.512269</a>
Rights
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Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
*DNA methylation
*Epigenesis
2014
5-hmC
5-Methylcytosine/analogs & derivatives
Chondrocytes
Chondrocytes/chemistry/*metabolism
Cytokine
Cytosine/*analogs & derivatives/analysis/metabolism
Department of Anatomy & Neurobiology
Dioxygenase
DNA Methylation
DNA-Binding Proteins/*biosynthesis/genetics
Epigenetics
Genetic
Haqqi Tariq M
Haseeb Abdul
Humans
IL-1
Interleukin-1beta/pharmacology/*physiology
Isocitrate Dehydrogenase/*biosynthesis/genetics
Ketoglutaric Acids/*metabolism
Makki Mohammad Shahidul
Messenger/biosynthesis/genetics
Mixed Function Oxygenases
NEOMED College of Medicine
Primary Cell Culture
Proto-Oncogene Proteins/*biosynthesis/genetics
RNA
The Journal of biological chemistry
TNF-alpha
Tumor Necrosis Factor-alpha/pharmacology/physiology