Sebastian Lunke1, Scott Maxwell1,2, Ishant Khurana1,2, Harikrishnan K N1,2,3, Jun Okabe1,2, Keith Al-Hasani1,2, Assam El-Osta4,5,6,7,8,9,10,11. 1. Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia. 2. Epigenetics in Human Health and Disease Laboratory, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia. 3. Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia. 4. Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia. sam.el-osta@monash.edu. 5. Epigenetics in Human Health and Disease Laboratory, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia. sam.el-osta@monash.edu. 6. Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia. sam.el-osta@monash.edu. 7. Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia. sam.el-osta@monash.edu. 8. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR. sam.el-osta@monash.edu. 9. Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, 3/F Lui Che Woo Clinical Sciences Building, 30-32 Ngan Shing Street, Sha Tin, Hong Kong SAR. sam.el-osta@monash.edu. 10. Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR. sam.el-osta@monash.edu. 11. Biomedical Laboratory Science, Department of Technology, Faculty of Health, University College Copenhagen, Copenhagen, Denmark. sam.el-osta@monash.edu.
Abstract
BACKGROUND: Valproic acid (VPA) is one of the most commonly used anti-epileptic drugs with pharmacological actions on GABA and blocking voltage-gated ion channels. VPA also inhibits histone deacetylase (HDAC) activity. Suberoylanilide hydroxamic acid is also a member of a larger class of compounds that inhibit HDACs. At the time of this article, there are 123 active international clinical trials for VPA (also known as valproate, convulex, divalproex, and depakote) and SAHA (vorinostat, zolinza). While it is well known that VPA and SAHA influence the accumulation of acetylated lysine residues on histones, their true epigenetic complexity remains poorly understood. RESULTS: Primary human cells were exposed to VPA and SAHA to understand the extent of histone acetylation (H3K9/14ac) using chromatin immunoprecipitation followed by sequencing (ChIP-seq). Because histone acetylation is often associated with modification of lysine methylation, we also examined H3K4me3 and H3K9me3. To assess the influence of the HDAC inhibitors on gene expression, we used RNA sequencing (RNA-seq). ChIP-seq reveals a distribution of histone modifications that is robust and more broadly regulated than previously anticipated by VPA and SAHA. Histone acetylation is a characteristic of the pharmacological inhibitors that influenced gene expression. Surprisingly, we observed histone deacetylation by VPA stimulation is a predominant signature following SAHA exposure and thus defines an acetylation/deacetylation (Ac/Dc) axis. ChIP-seq reveals regionalisation of histone acetylation by VPA and broader deacetylation by SAHA. Independent experiments confirm H3K9/14 deacetylation of NFκB target genes by SAHA. CONCLUSIONS: The results provide an important framework for understanding the Ac/Dc axis by highlighting a broader complexity of histone modifications by the most established and efficacious anti-epileptic medication in this class, VPA and comparison with the broad spectrum HDAC inhibitor, SAHA.
BACKGROUND: Valproic acid (VPA) is one of the most commonly used anti-epileptic drugs with pharmacological actions on GABA and blocking voltage-gated ion channels. VPA also inhibits histone deacetylase (HDAC) activity. Suberoylanilide hydroxamic acid is also a member of a larger class of compounds that inhibit HDACs. At the time of this article, there are 123 active international clinical trials for VPA (also known as valproate, convulex, divalproex, and depakote) and SAHA (vorinostat, zolinza). While it is well known that VPA and SAHA influence the accumulation of acetylated lysine residues on histones, their true epigenetic complexity remains poorly understood. RESULTS: Primary human cells were exposed to VPA and SAHA to understand the extent of histone acetylation (H3K9/14ac) using chromatin immunoprecipitation followed by sequencing (ChIP-seq). Because histone acetylation is often associated with modification of lysine methylation, we also examined H3K4me3 and H3K9me3. To assess the influence of the HDAC inhibitors on gene expression, we used RNA sequencing (RNA-seq). ChIP-seq reveals a distribution of histone modifications that is robust and more broadly regulated than previously anticipated by VPA and SAHA. Histone acetylation is a characteristic of the pharmacological inhibitors that influenced gene expression. Surprisingly, we observed histone deacetylation by VPA stimulation is a predominant signature following SAHA exposure and thus defines an acetylation/deacetylation (Ac/Dc) axis. ChIP-seq reveals regionalisation of histone acetylation by VPA and broader deacetylation by SAHA. Independent experiments confirm H3K9/14 deacetylation of NFκB target genes by SAHA. CONCLUSIONS: The results provide an important framework for understanding the Ac/Dc axis by highlighting a broader complexity of histone modifications by the most established and efficacious anti-epileptic medication in this class, VPA and comparison with the broad spectrum HDAC inhibitor, SAHA.
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