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Histone deacetylase inhibitors reactivate silenced transgene in vivo

Gene Therapy volume 26, pages 75–85 (2019)Cite this article

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Abstract

Gene silencing for plasmid-based vectors and the underlying mechanism are critical factors for development of effective gene therapy. The objective of this study is to explore the role of epigenetic regulation for transgene expression. Two reporter genes, mouse interleukin 10 and human secreted alkaline phosphatase under the control of human cytomegalovirus immediate early promoter for expression, were delivered to mouse liver by hrodydynamics-based procedure and reporter gene expression was monitored. Reporter gene expression reached its peak level one day after gene delivery and declined progressively thereafter, reaching the minimal level in about 3 weeks. Intra-peritoneal injection of vorinostat, valproic acid or sodium butyrate, the known histone deacetylase inhibitors, resulted in a dose-dependent reactivation of reporter gene expression. Repeated administration of histone deacetylase inhibitors blocked gene silencing and maintained reporter gene expression. Mechanistic studies reveal that reactivation of reporter genes is corelated with hyperacetylation of histones H3 and H4, and elevated binding of TATA-box binding protein to the promoter region. These results suggest that epigenetic regulation plays a critical role in controlling transgene expression in vivo and demonstrate that enzymes involved in epigenetic regulation such as histone deacetylase could serve as a target to achieve controlled transgene expression for gene therapy.

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Acknowledgements

This study is supported by grants from NIH (RO1EB007357 and RO1HL098295). We are grateful to Dr. Leping Li at the National Institute of Environmental Health Sciences for providing the sequence information regarding the transcription factor binding sites in CMV promotor.

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  1. Chunbo Zhang

    Present address: School of Pharmacy, Nanchang University, Nanchang, Jiangxi, 330031, China

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  1. Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, Athens, Georgia, 30602, USA

    Chunbo Zhang, Guisheng Zhang & Dexi Liu

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Correspondence to Dexi Liu.

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Zhang, C., Zhang, G. & Liu, D. Histone deacetylase inhibitors reactivate silenced transgene in vivo. Gene Ther 26, 75–85 (2019). https://doi.org/10.1038/s41434-018-0053-4

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