Abstract
ABSTRACTHuman embryonic stem cells (hESCs) depend on glycolysis for energy and substrates for biosynthesis. To understand the mechanisms governing the metabolism of hESCs, we investigated the transcriptional regulation of glucose transporter 1 (GLUT1, SLC2A1), a key glycolytic gene to maintain pluripotency. By combining the genome-wide data of binding sites of the core pluripotency factors (SOX2, OCT4, NANOG, denoted SON), chromosomal interaction and histone modification in hESCs, we identified a potential enhancer of the GLUT1 gene in hESCs, denoted GLUT1 enhancer (GE) element. GE interacts with the promoter of GLUT1, and the deletion of GE significantly reduces the expression of GLUT1, glucose uptake and glycolysis of hESCs, confirming that GE is an enhancer of GLUT1 in hESCs. In addition, the mutation of SON binding motifs within GE reduced the expression of GLUT1 as well as the interaction between GE and GLUT1 promoter, indicating that the binding of SON to GE is important for its activity. Therefore, SON promotes glucose uptake and glycolysis in hESCs by inducing GLUT1 expression through directly activating the enhancer of GLUT1.
Highlights
Human embryonic stem cells can undergo unlimited self-renewal and maintain the pluripotency to differentiate into all lineages of cells of the human body (De Los Angeles et al, 2015)
To understand the mechanisms governing the metabolism of Human embryonic stem cells (hESCs), we investigated the transcriptional regulation of glucose transporter 1 (GLUT1, SLC2A1), a key glycolytic gene to maintain pluripotency
Another reason we focused on GLUT1 enhancer (GE) was that the analysis of the ChIP-seq data of SOX2, octamer-binding transcription factor 4 (OCT4), and NANOG denoted SON, in hESCs indicated the co-binding of SON to GE (Fig. 1A and 1B)
Summary
Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and maintain the pluripotency to differentiate into all lineages of cells of the human body (De Los Angeles et al, 2015). This metabolic signature of pluripotency is similar to the Warburg effect in human cancers and is primarily dependent on glycolysis (Shyh-Chang and Daley, 2015). In this context, glycolysis produces ATP at a faster rate than oxidative phosphorylation, and glycolytic intermediates are biosynthesis substrates required for unlimited selfrenewal of hESCs (Shyh-Chang and Daley, 2015). While the core transcriptional factors SRY (sex determining region Y)-box 2 (SOX2), octamer-binding transcription factor 4 (OCT4), and NANOG, collectively denoted SON, are required to maintain pluripotency (Chen et al, 2008), their roles in maintaining the metabolic profile of ESCs remain unclear
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