DNA replication coupled mechanisms that control cell fate transitions (360G-Wellcome-334958_Z_25_Z)

Developmental signalling cues drive major chromatin and transcriptional changes, via the combined action of transcription factors and chromatin effectors. However, it remains unclear how such signalling cues induce the earliest chromatin changes that commit cells to differentiation. We have established a system in human induced pluripotent stem cells (iPSCs) to investigate the mechanisms of cell fate transitions in replicating cells and open this area for exploration. We recently identified a set of proteins that are rapidly recruited in the vicinity of replication forks when iPSCs are exposed to signals that induce differentiation, and that are essential for differentiation. We will use genetics, biochemistry, and microscopy to identify causative factors and understand how these proteins rapidly respond to differentiation signals. We will develop a new tool to target degradation of such factors, specifically in the vicinity of replication forks, to identify replication coupled mechanisms that change the chromatin landscape and drive differentiation. The utilisation of cutting-edge technologies and new approaches will make this possible for the first time. With our previous work, we are in a unique position to explore which factors are essential for this process and how this could be manipulated to guide iPSC differentiation for future cell therapies.