Cited2, a transcriptional modulator protein, regulates metabolism in murine embryonic stem cells

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.