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RNA sequencing for tumor-initiating stem-like cells (TICs) treated with all-trans retinoic acid (ATRA) and suberoylanilide hydroxamic acid (SAHA)

ABSTRACT: TIC population plays a vital role for tumor recurrence and therapy resistnace. In this study, we identified the drug combination of ATRA and SAHA can specifically target TICs in vitro and in vivo. By conducting RNA sequencing and genome-wide transcriptome analysis, we comprehesively illustrate that the combination treatment epigenetically regulates TICs.

ORGANISM(S): Mus musculus

PROVIDER: GSE78139 | GEO | 2019/12/31

REPOSITORIES: GEO

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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

RNA sequencing for tumor-initiating stem-like cells (TICs) treated with all-trans retinoic acid (ATRA) and suberoylanilide hydroxamic acid (SAHA)

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