PMID:28262547

Citation	Nishimura, K, Aizawa, S, Nugroho, FL, Shiomitsu, E, Tran, YT, Bui, PL, Borisova, E, Sakuragi, Y, Takada, H, Kurisaki, A, Hayashi, Y, Fukuda, A, Nakanishi, M and Hisatake, K (2017) A Role for KLF4 in Promoting the Metabolic Shift via TCL1 during Induced Pluripotent Stem Cell Generation. Stem Cell Reports 8:787-801
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.
Links	PubMed Online version:10.1016/j.stemcr.2017.01.026
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:KLF4		GO:0000981: RNA polymerase II transcription factor activity, sequence-specific DNA binding	ECO:0000314:		F		MOUSE KLF4 // Fig 4 and "qRT-PCR showed that the high level of KLF4 or expression of exogenous TCL1 in iPSCs(Low-K) is accompanied by increased mRNA expression levels of glucose transporter (Glut1), pyruvate kinase M2 (Pkm2), and lactate dehydrogenase A (Ldha) ( Figure 6F)." KLF4 upregulates Tcl1 expression to enhance AKT activity, thus increasing the expression of other glycolytic protein.	complete CACAO 12382
MOUSE:AKT1		GO:0006096: glycolytic process	ECO:0000315:		P		MOUSE AKT1 (AKT) // AKT inhibitor, MK2206, significantly diminished the uptake of glucose and lactate production (Figures 6C and 6D).	complete CACAO 12384
MOUSE:TCL1A		GO:0032148: activation of protein kinase B activity	ECO:0000315:		P		MOUSE TCL1A (TCL1) // As shown in Figures 5A and 5B, we found that an active form of AKT, phosphorylated at Ser473, is increased in iPSCs(High-K) or when exogenous TCL1 was expressed in iPSCs(Low-K), suggesting that KLF4-induced TCL1 enhances the AKT activity.	complete CACAO 12383
MOUSE:TCL1A		GO:0090324: negative regulation of oxidative phosphorylation	ECO:0000315:		P		MOUSE TCL1A (TCL1) // TCL1 decreases oxidative phosphorylation by antagonizing PnPase (Fig. 7G).	complete CACAO 12388
MOUSE:TCL1A		GO:0008283: cell proliferation	ECO:0000315:		P		Although the AKT pathway is involved in cell proliferation and survival (Manning and Cantley, 2007), iPSCs(Low-K) and iPSCs(High-K), which differ in AKT activity (Figures 5A and 5B), showed unexpectedly similar rates of cell proliferation (Figure 6A), by author. Mouse TCL1A (TCL 1) EC: IMP	complete CACAO 12853
MOUSE:TCL1A		GO:0045821: positive regulation of glycolytic process	ECO:0000315:		P		the media of iPSCs(High-K) turned yellow faster than that of iPSCs(Low-K) (Figure 6B). This often indicates lactic acidosis resulting from enhanced glycolysis. Both glucose uptake and lactate production were higher in iPSCs(High-K) than in iPSCs(Low-K) (Figures 6C and 6D). KLF4 enhances glycolysis during the transition from iPSCs(Low-K) to iPSCs(High-K), in large part through the TCL1-AKT pathway. P: (TCL1) O: Mouse TCL1A (TCL 1)	complete CACAO 12735

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