The Characterization Of Chromatin Modifying Genes In Dengue Virus Infected Human Monocytic Cells: Implication In Modulating Inflammation

Acker, Zachary
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University of Hawaii at Manoa
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Epigenetic control of gene expression is a complex mechanism and involves DNA methylation and histone acetylation mediated by opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs) enzymes. Epigenetic modifications are well characterized in Multiple Sclerosis, cancer, diabetes and asthma. Altered HDAC activity is linked to cytokines production in bacterial and fungal infections. However, the data on the epigenetic modifications in virus infections are not well characterized. Dengue virus has become a significant public health concern and the antibody-dependent enchancement (ADE) phenomenon further complicates the dengue pathogenesis by potentiating inflammation. The objective of this study was to determine the expression profiles of complete panel of histone modifier genes in human monocytic cells (THP1) following dengue infection. THP1 cells were infected with DEN2-NGC strain directly or under ADE conditions (4G2 antibody). Total RNA from mock and infected cells was used for Human Epigenetic Chromatin Modification Enzyme for RT2 ProfilerTM Array to detect the expression of 84 chromatin modifying enzymes. Further, THP1 cells were treated with HDAC (TSA) and HAT (Anacardic Acid) inhibitors and virus titers and cytokine levels were measured. Our results show that Dengue infection caused changes in 10-20% of genes involved with chromatin modification. Differences in the expression profiles were also observed between Dengue infection with and without ADE conditions. Experiments are ongoing to analyze effects of inhibiting HDACs and HATs on the expression key inflammatory cytokines associated with dengue pathogenesis, IL- 8 and TNF - α This is the first report describing changes in complete panel of histone modifying enzymes and associated transcription factors in Dengue infection. Based on the literature indicating a strong association between changes in HDAC/HAT levels with production of inflammatory cytokines in other inflammatory diseases, we speculate that inflammatory response induced during Dengue infection is at least partially modulated by epigenetic mechanisms.
iii, 43 pages
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