Dataset Information

Dose-responsive gene expression in suberoylanilide hydroxamic acid-treated resting CD4+ T cells.

ABSTRACT: DESIGN:Persistent latently infected CD4 T cells represent a major obstacle to HIV eradication. Histone deacetylase inhibitors (HDACis) are a proposed activation therapy. However, off-target effects on gene expression in host immune cells are poorly understood. We hypothesized that HDACi-modulated genes would be best identified with a dose-response analysis. METHODS:Resting primary CD4 T cells were treated with 0.34, 1, 3, or 10??mol/l of the HDACi, suberoylanilide hydroxamic acid (SAHA), for 24?h and subjected to microarray gene expression analysis. Genes with dose-correlated expression were filtered to identify a subset with consistent up or downregulation at each SAHA dose. Histone modifications were characterized in six SAHA dose-responsive genes by chromatin immunoprecipitation (ChIP-RT-qPCR). RESULTS:A large number of genes were shown to be upregulated (N?=?657) or downregulated (N?=?725) by SAHA in a dose-responsive manner (FDR-corrected P-value???0.5, fold change ?|2|). Several genes (e.g. CINNAL1, DPEP2, H1F0, IRGM, PHF15, and SELL) are potential in-vivo biomarkers of SAHA activity. SAHA dose-responsive genes included transcription factors, HIV restriction factors, histone methyltransferases, and host proteins that interact with HIV. Pathway analysis suggested net downregulation of T-cell activation with increasing SAHA dose. Histone acetylation was not correlated with host gene expression, but plausible alternative mechanisms for SAHA-modulated gene expression were identified. CONCLUSION:Numerous genes in CD4 T cells are modulated by SAHA in a dose-responsive manner, including genes that may negatively influence HIV activation from latency. Our study suggests that SAHA influences gene expression through a confluence of several mechanisms, including histone modification, and altered expression and activity of transcription factors.

SUBMITTER: Reardon B

PROVIDER: S-EPMC4917679 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Dose-responsive gene expression in suberoylanilide hydroxamic acid-treated resting CD4+ T cells.

Reardon Brian B Beliakova-Bethell Nadejda N Spina Celsa A CA Singhania Akul A Margolis David M DM Richman Douglas R DR Woelk Christopher H CH

AIDS (London, England) 20151101 17

<h4>Design</h4>Persistent latently infected CD4 T cells represent a major obstacle to HIV eradication. Histone deacetylase inhibitors (HDACis) are a proposed activation therapy. However, off-target effects on gene expression in host immune cells are poorly understood. We hypothesized that HDACi-modulated genes would be best identified with a dose-response analysis.<h4>Methods</h4>Resting primary CD4 T cells were treated with 0.34, 1, 3, or 10 μmol/l of the HDACi, suberoylanilide hydroxamic acid ...[more]

PMID: 26258524

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Project description:Design: Persistent latently infected CD4+ T cells represent a major obstacle to HIV eradication. Histone deacetylase inhibitors (HDACis) are a promising activation therapy in a “shock and kill” strategy. However, off-target effects of HDACis on host gene expression are poorly understood in primary cells of the immune system. We hypothesized that HDACi-modulated genes would be best identified with a dose response analysis. Methods: Resting primary CD4+ T cells were treated with increasing concentrations (0.34, 1, 3, or 10 μM) of the HDACi, suberoylanilide hydroxamic acid (SAHA), for 24 hours and then subjected to microarray gene expression analysis. Genes with dose-correlated expression were identified with a likelihood ratio test using Isogene GX and a subset of these genes with a consistent trend of up or downregulation at each dose of SAHA were identified as dose-responsive. Histone modifications were characterized in promoter regions of the top 6 SAHA dose-responsive genes by RT-qPCR analysis of immunopreciptated chromatin (ChIP). Results: A large number of genes were shown to be up (N=657) or down (N=725) regulated by SAHA in a dose-responsive manner (FDR p-value < 0.05 and fold change ≥ |2|). Several of these genes (CTNNAL1, DPEP2, H1F0, IRGM, PHF15, and SELL) are potential in vivo biomarkers of SAHA activity. SAHA dose-responsive gene categories included transcription factors, HIV restriction factors, histone methyltransferases, and host proteins that interact with HIV proteins or the HIV LTR. Pathway analysis suggested net downregulation of T cell activation with increasing SAHA dose. Histone acetylation was not correlated with host expression, but plausible alternative mechanisms for SAHA-modulated expression were identified. Conclusions: Numerous host genes in CD4+ T cells are modulated by SAHA in a dose-responsive manner, including genes that may negatively influence HIV activation from latency. Our study suggests that SAHA influences gene expression through a confluence of several mechanisms, including histone acetylation, histone methylation, and altered expression and activity of transcription factors.

Dataset Information

Dose-responsive gene expression in suberoylanilide hydroxamic acid-treated resting CD4+ T cells.

Publications

Dose-responsive gene expression in suberoylanilide hydroxamic acid-treated resting CD4+ T cells.

Similar Datasets

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