Enhanced MyoD-Induced Transdifferentiation to a Myogenic
Lineage by Fusion to a Potent Transactivation Domain
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Abstract
Genetic reprogramming
holds great potential for disease modeling,
drug screening, and regenerative medicine. Genetic reprogramming of
mammalian cells is typically achieved by forced expression of natural
transcription factors that control master gene networks and cell lineage
specification. However, in many instances, the natural transcription
factors do not induce a sufficiently robust response to completely
reprogram cell phenotype. In this study, we demonstrate that protein
engineering of the master transcription factor MyoD can enhance the
conversion of human dermal fibroblasts and adult stem cells to a skeletal
myocyte phenotype. Fusion of potent transcriptional activation domains
to MyoD led to increased myogenic gene expression, myofiber formation,
cell fusion, and global reprogramming of the myogenic gene network.
This work supports a general strategy for synthetically enhancing
the direct conversion between cell types that can be applied in both
synthetic biology and regenerative medicine