title: Radical acceleration of nuclear reprogramming by chromatin remodeling with the transactivation domain of MyoD.
abstract: Induced pluripotent stem cells (iPSCs) can be created by reprogramming differentiated cells through introduction of defined genes, most commonly Oct4, Sox2, Klf4, and c-Myc (OSKM). However, this process is slow and extremely inefficient. Here, we demonstrate radical acceleration of iPSC creation with a fusion gene between Oct4 and the powerful transactivation domain (TAD) of MyoD (M(3)O). Transduction of M(3) O as well as Sox2, Klf4, and c-Myc into fibroblasts effectively remodeled patterns of DNA methylation, chromatin accessibility, histone modifications, and protein binding at pluripotency genes, raising the efficiency of making mouse and human iPSCs more than 50-fold in comparison to OSKM. These results identified that one of the most critical barriers to iPSC creation is poor chromatin accessibility and protein recruitment to pluripotency genes. The MyoD TAD has a capability of overcoming this problem. Our approach of fusing TADs to unrelated transcription factors has far-reaching implications as a powerful tool for transcriptional reprogramming beyond application to iPSC technology.
authors: Stem Cell Institute, Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors: Hiroyuki
authors: H
authors: Hirai
authors: Tetsuya
authors: T
authors: Tani
authors: Nobuko
authors: N
authors: Katoku-Kikyo
authors: Steven
authors: S
authors: Kellner
authors: Peter
authors: P
authors: Karian
authors: Meri
authors: M
authors: Firpo
authors: Nobuaki
authors: N
authors: Kikyo
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming; D042002:Chromatin Assembly and Disassembly; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000502:physiology*; D000090062:Kruppel-Like Factor 4; D051379:Mice; D017570:MyoD Protein / Q000235:genetics*; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D017434:Protein Structure, Tertiary; D015533:Transcriptional Activation
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C494174:Pou5f1 protein, mouse