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Stem Cell Reports ; 8(3): 787-801, 2017 03 14.
Article in English | MEDLINE | ID: mdl-28262547

ABSTRACT

Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) is accompanied by morphological, functional, and metabolic alterations before acquisition of full pluripotency. Although the genome-wide effects of the reprogramming factors on gene expression are well documented, precise mechanisms by which gene expression changes evoke phenotypic responses remain to be determined. We used a Sendai virus-based system that permits reprogramming to progress in a strictly KLF4-dependent manner to screen for KLF4 target genes that are critical for the progression of reprogramming. The screening identified Tcl1 as a critical target gene that directs the metabolic shift from oxidative phosphorylation to glycolysis. KLF4-induced TCL1 employs a two-pronged mechanism, whereby TCL1 activates AKT to enhance glycolysis and counteracts PnPase to diminish oxidative phosphorylation. These regulatory mechanisms described here highlight a central role for a reprogramming factor in orchestrating the metabolic shift toward the acquisition of pluripotency during iPSC generation.


Subject(s)
Cellular Reprogramming , Energy Metabolism , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/metabolism , Kruppel-Like Transcription Factors/metabolism , Proto-Oncogene Proteins/metabolism , Animals , Cellular Reprogramming/genetics , Gene Expression Profiling , Gene Expression Regulation , Glycolysis , Kruppel-Like Factor 4 , Kruppel-Like Transcription Factors/genetics , Mice , Mitochondria/genetics , Mitochondria/metabolism , Oxidative Phosphorylation , Protein Binding , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction
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