Histone deacetylase inhibitors reactivate silenced transgene in vivo
Autor: | Chunbo Zhang, Dexi Liu, Guisheng Zhang |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Transgene Genetic Vectors Gene delivery Histone Deacetylases Epigenesis Genetic Histones Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Genes Reporter Genetics medicine Animals Humans Gene silencing Gene Silencing Transgenes Promoter Regions Genetic Molecular Biology Vorinostat Reporter gene biology Valproic Acid Sodium butyrate Alkaline Phosphatase Interleukin-10 Cell biology Histone Deacetylase Inhibitors 030104 developmental biology Histone Gene Expression Regulation chemistry 030220 oncology & carcinogenesis biology.protein Molecular Medicine Female Histone deacetylase medicine.drug |
Zdroj: | Gene Therapy. 26:75-85 |
ISSN: | 1476-5462 0969-7128 |
Popis: | 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. |
Databáze: | OpenAIRE |
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