Transcription factors are central for establishing the cell type-specific gene expression patterns that characterize each of the hundreds of different cell types in developing and adult mammals. Transcription factors are often regulated by signaling pathways, which affect the activity of these factors and ensure appropriate transcriptional responses to developmental and environmental cues. Our preliminary studies indicate that a transcription factor central to embryonic stem cell self-renewal, SOX2, is modified by addition of an O-linked N-acetylglucosamine sugar to serine residue 248 and threonine residue 213. This modification is mediated by the enzyme OGT, which is a central player in the nutrient sensing pathway that detects levels of glucose and other nutrients. We propose to investigate the role of this post-translational modification of SOX2 in self-renewal, to better understand how metabolic pathways impact gene expression in pluripotent cells.
Regulation of SOX2 by O-GlcNAcylation in pluripotent stem cells. We have found that the enzyme OGT, which is central in the hexosamine biosynthesis nutrient-sensing pathway, post-translationally modifies the pluripotency transcription factor SOX2 in embryonic stem cells (ESCs). Mutations of the two modified residues, S248 and T213, have opposing effects on SOX2 function. These data suggest that ESCs use this pathway to monitor nutrient status and decide whether to self-renew or differentiate. We propose experiments to gain a molecular understanding of the OGT-dependent modification of SOX2 in ESC self-renewal.
