title: Identifying the Biphasic Role of Calcineurin/NFAT Signaling Enables Replacement of Sox2 in Somatic Cell Reprogramming.
abstract: Induction of pluripotency with defined factors (octamer-binding transcription factor 4 [Oct4], SRY (sex determining region Y)-box 2 [Sox2], Kruppel-like factor 4 [Klf4], c-Myc) raises hopes for successful clinical trials. Despite considerable efforts, the molecular mechanism of reprogramming remains poorly understood. The aim of the present study was to identify the role of calcineurin/nuclear factor of activated T cells (NFAT) in reprogramming. Our results demonstrated a biphasic role for calcineurin/NFAT signaling during reprogramming. In the early phase of reprogramming, calcineurin activity is required to maintain proper cell cycle division and for mesenchymal-epithelial transition. In the late phase, calcineurin exerts a negative effect that is mediated by NFATc2. NFATc2 interacts with Hdac3, Ezh2, and Suv39h1 to increase H3K9me3 and H3K27me3 over the Sox2 enhancer and Klf2 promoter, respectively, resulting in the downregulation of their expression. Moreover, Gαq was identified as a positive upstream regulator for calcineurin. The Gαq/calcineurin/NFATc2 axis negatively regulates the late step of reprogramming. By inhibiting NFATc2 or calcineurin, induced pluripotent stem cells could be established without exogenous Sox2. Thus, the present study revealed another regulatory level of reprogramming, and proposes a biological axis that could be useful for cancer therapy. Stem Cells 2017;35:1162-1175.
authors.affiliation: Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto, Japan.
authors.forename: Sherif
authors.initials: S
authors.lastname: Khodeer
authors.affiliation: Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Era
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D055785:Gene Knockdown Techniques; D006570:Heterochromatin / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D018797:Cell Cycle Proteins; D006570:Heterochromatin; C498314:Klf2 protein, mouse; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050778:NFATC Transcription Factors; D043562:Receptors, G-Protein-Coupled; D055748:SOXB1 Transcription Factors; D019703:Calcineurin
keywords: Calcineurin; Induced pluripotent stem cells; Nuclear factor of activated T cells; Reprogramming; SRY (sex determining region Y)-box 2