The OCT4-RNA Interactome in Pluripotent Stem Cells Reveals Direct Translational Regulation of the AKT-Pathway Genes by OCT4

Post-transcriptional gene regulation emerges to be vital for establishing and maintaining the pluripotency of pluripotent stem cells (PSCs), but the underlying molecular basis remains unclear. Here, by genome-wide deciphering the OCT4-RNA interactome with the high-throughput sequencing of cross-linking immunoprecipitation cDNA library (HITS-CLIP), we revealed OCT4 as a bona fide RNA-binding protein (RBP) in human embryonic stem cells that bound preferentially to the 5’-UTR, 3’-UTR and CDS regions of mRNAs. In addition, multiple known proteins participating in IRES-mediated translation initiation were detected in the OCT4-protein interactome. Remarkably, OCT4 bound to the G-rich elements in the 5’-UTR of AKT1 and multiple PI3K/AKT pathway gene mRNAs, and promoted their translation initiation via IRES-mediated pathways under stress conditions such as hypoxia. Our results establish OCT4 as a novel key player for post-transcriptional/translational regulation that critically contributes to the survival and self-renewal of PSCs.