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This paper establishes a regulatory cascade in which elevated levels of glutathione, synthesized from extracellular glutamine, maintains a reduced environment that is required for OCT4 stability and DNA binding. The first report to describe that glutamine metabolic flux is required for the activity and maintenance of a core pluripotency factor, and therefore pluripotency.
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43• Marsboom, G., Zhang, G.-F., Pohl-Avila, N., Zhang, Y., Yuan, Y., Kang, H., Hao, B., Brunengraber, H., Malik, A.B., Rehman, J., Glutamine metabolism regulates the pluripotency transcription factor OCT4. Cell Rep 16 (2016), 323–332 This paper establishes a regulatory cascade in which elevated levels of glutathione, synthesized from extracellular glutamine, maintains a reduced environment that is required for OCT4 stability and DNA binding. The first report to describe that glutamine metabolic flux is required for the activity and maintenance of a core pluripotency factor, and therefore pluripotency.
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Folmes, C.D.L., Nelson, T.J., Martinez-Fernandez, A., Arrell, D.K., Lindor, J.Z., Dzeja, P.P., Ikeda, Y., Perez-Terzic, C., Terzic, A., Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab 14 (2011), 264–271.
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48
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Polo, J.M., Anderssen, E., Walsh, R.M., Schwarz, B.A., Nefzger, C.M., Lim, S.M., Borkent, M., Apostolou, E., Alaei, S., Cloutier, J., et al. A molecular roadmap of reprogramming somatic cells into iPS cells. Cell 151 (2012), 1617–1632.
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This study was the first to demonstrate that elevated levels of ROS are required in early IPSC formation to establish an oxidative state that allows for NRF2 to initiate the aerobic glycolytic program through HIF1α.
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51• Hawkins, K.E., Joy, S., Delhove, J.M.K.M., Kotiadis, V.N., Fernandez, E., Fitzpatrick, L.M., Whiteford, J.R., King, P.J., Bolanos, J.P., Duchen, M.R., et al. NRF2 orchestrates the metabolic shift during induced pluripotent stem cell reprogramming. Cell Rep 14 (2016), 1883–1891 This study was the first to demonstrate that elevated levels of ROS are required in early IPSC formation to establish an oxidative state that allows for NRF2 to initiate the aerobic glycolytic program through HIF1α.
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55
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The authors document a burst of oxidative phosphorylation, caused by PGC-1 and EERα/γ, within SCA1-/CD34-cells as the earliest described required event of reprograming, and this burst induces the establishment of aerobic glycolysis in IPSC formation.
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55•• Kida, Y.S., Kawamura, T., Wei, Z., Sogo, T., Jacinto, S., Shigeno, A., Kushige, H., Yoshihara, E., Liddle, C., Ecker, J.R., et al. ERRs mediate a metabolic switch required for somatic cell reprogramming to pluripotency. Cell Stem Cell 16 (2015), 547–555 The authors document a burst of oxidative phosphorylation, caused by PGC-1 and EERα/γ, within SCA1-/CD34-cells as the earliest described required event of reprograming, and this burst induces the establishment of aerobic glycolysis in IPSC formation.
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