An engineered epigenetic transgene switch in mammalian cells.
In multicellular systems cell identity is imprinted by epigenetic regulation circuits, which determine the global transcriptome of adult cells in a cell phenotype-specific manner. By combining two repressors, which control each other's expression, we have developed a mammalian epigenetic circuitry able to switch between two stable transgene expression states after transient administration of two alternate drugs. Engineered Chinese hamster ovary cells (CHO-K1) showed toggle switch-specific expression profiles of a human glycoprotein in culture, as well as after microencapsulation and implantation into mice. Switch dynamics and expression stability could be predicted with mathematical models. Epigenetic transgene control through toggle switches is an important tool for engineering artificial gene networks in mammalian cells.
Kramer
Beat P
BP
Institute of Biotechnology, Swiss Federal Institute of Technology, ETH Zurich, CH-8093 Zurich, Switzerland.
Viretta
Alessandro Usseglio
AU
Daoud-El-Baba
Marie
M
Aubel
Dominique
D
Weber
Wilfried
W
Fussenegger
Martin
M
D000469:Alkaline Phosphatase / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D016466:CHO Cells; D017690:Cell Transplantation; D006224:Cricetinae; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D004917:Erythromycin / Q000494:pharmacology; D005786:Gene Expression Regulation; D020868:Gene Silencing / Q000187:drug effects; D005813:Genes, Synthetic; D005818:Genetic Engineering; D051379:Mice; D025762:Pristinamycin / Q000494:pharmacology; D019076:Transgenes / Q000235:genetics*
D025762:Pristinamycin; D004917:Erythromycin; D000469:Alkaline Phosphatase