Abstract
CREB-binding protein (CBP)/p300 interacting transactivator with glutamic acid (Glu) and aspartic acid (Asp)-tail 2 (Cited2) was recently shown to be essential for gluconeogenesis in the adult mouse. The metabolic function of Cited2 in mouse embryonic stem cells (mESCs) remains elusive. In the current study, the metabolism of glucose was investigated in mESCs, which contained a deletion in the gene for Cited2 (Cited2(Δ/-)). Compared with its parental wild type counterpart, Cited2(Δ/-) ESCs have enhanced glycolysis, alternations in mitochondria morphology, reduced glucose oxidation, and decreased ATP content. Cited2 is recruited to the hexokinase 1 (HK1) gene promoter to regulate transcription of HK1, which coordinates glucose metabolism in wild type ESCs. Reduced glucose oxidation and enhanced glycolytic activity in Cited2(Δ/-) ESCs correlates with defective differentiation during hypoxia, which is reflected in an increased expression of pluripotency marker (Oct4) and epiblast marker (Fgf5) and decreased expression of lineage specification markers (T, Gata-6, and Cdx2). Knockdown of hypoxia inducible factor-1α in Cited2(Δ/-) ESCs re-initiates the expression of differentiation markers T and Gata-6. Taken together, a deletion of Cited2 in mESCs results in abnormal mitochondrial morphology and impaired glucose metabolism, which correlates with a defective cell fate decision.
Highlights
The function of hypoxia inducible factor (HIF)-1, a master regulator of metabolism, is in part modulated by Cited2
Enhanced Aerobic Glycolysis and Reduced Glucose Oxidation in Undifferentiated Cited2⌬/Ϫ ESCs—Media in the three independent Cited2⌬/Ϫ ESC clones previously generated via homologous recombination was noted to become acidic during EBinduced differentiation, as compared with the WT counterpart, suggesting that deletion of Cited2 may affect the rate of glucose conversion to lactate in ESCs
Besides conversion to lactate by lactate dehydrogenase (LDH), glucose-derived pyruvate can be oxidized in the mitochondria to acetyl-CoA by the pyruvate dehydrogenase complex, which can be oxidized to CO2 in the tricarboxylic acid (TCA) cycle
Summary
The function of HIF-1, a master regulator of metabolism, is in part modulated by Cited. Results: Deletion of Cited in mESCs results in impaired mitochondria morphology, reduced glucose oxidation, increased glycolysis, and defective mESC differentiation. Cited is recruited to the hexokinase 1 (HK1) gene promoter to regulate transcription of HK1, which coordinates glucose metabolism in wild type ESCs. Reduced glucose oxidation and enhanced glycolytic activity in Cited2⌬/؊ ESCs correlates with defective differentiation during hypoxia, which is reflected in an increased expression of pluripotency marker (Oct4) and epiblast marker (Fgf5) and decreased expression of lineage specification markers (T, Gata-6, and Cdx). Cited has been suggested as a crucial player in the regulation of gluconeogenesis, the role of Cited in glucose metabolism, especially glycolysis and oxidation phosphorylation in murine embryonic stem cells (mESC) remains elusive. Cited coordinates glucose metabolism, pluripotency, differentiation, and cell proliferation and is a potential target for metabolic reprogramming in ESCs
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