Monitoring rapid degradation of NANOG reveals UTP15 maintains pluripotency by regulating nascent transcripts

Master transcription factor (mTF) has been recognized as topmost regulatory hierarchy in cell fate determination. However, the direct transcriptional targets of mTFs, and how the interplay between these transcriptional targets and their associated RNA-binding proteins (RBPs) orchestrate the realisation of mTF functions, remain largely unknown. Here, we analysed transcriptional targets and their associated RBPs during acute depletion of NANOG in mouse embryonic stem cells (mESCs) using 5-ethynyluridine (EU) RNA metabolic labelling and click chemistry. We found that UTP15 is a sensor of NANOG transcriptional targets that maintains self-renewal of mESCs. Mechanistically, UTP15 is recruited to chromatin by NANOG transcriptional targets to maintain transcription of pluripotency-related genes. In conclusion, we provide a new paradigm to study the function of mTF and establish the mTF-nascent RNA-RBP axis that regulates cell fate decisions.