A Role for KLF4 in Promoting the Metabolic Shift via TCL1 during Induced Pluripotent Stem Cell Generation

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. [Display omitted] •KLF4 upregulates Tcl1 expression by directly binding to its enhancer and promoter•TCL1 enhances glycolysis by activating AKT during reprogramming•TCL1 reduces oxidative phosphorylation by counteracting PnPase during reprogramming•TCL1 promotes the metabolic shift to facilitate reprogramming In this article, Nishimura, Hisatake, and colleagues screened for genes regulated by KLF4 and identified Tcl1 as its major target gene, which promotes the metabolic shift from oxidative phosphorylation to glycolysis. KLF4-induced TCL1 activates AKT to enhance glycolysis and counteracts PnPase to diminish oxidative phosphorylation, thereby facilitating the progression of reprogramming toward full pluripotency.