Pluripotent stem cells have the ability to differentiate into many of the specialized cell types found in the body, a discovery which has driven a huge research effort to exploit these cells therapeutically. A key decision in the stem cell life cycle is whether to remain pluripotent (self-renew), or alternatively differentiate along a specific lineage. This process is primarily controlled by extracellular signalling cues, which control cell fate by implementing specific gene expression patterns.
We use mouse embryonic stem cells as a tractable model system to understand the role of signalling networks in promoting pluripotent and differentiated states. In particular, we are interested in uncovering phosphorylation and ubiquitylation-based mechanisms that control these processes. Our research may facilitate the application of stem cells in regenerative medicine, and reveal novel therapeutic strategies for human diseases arising from stem cell dysfunction.
In our recent work, we have elucidated a novel role for the Erk5 protein kinase in suppressing the transition of embryonic stem cells from a naïve to a primed state. Erk5 also plays a critical role in ESC lineage specification by suppressing cardiac-specific genes and cardiomyocyte differentiation. We also identified an “isoform switch” which enables BET bromodomain proteins to coordinate pluripotent exit with Smad2 signalling and mesendoderm differentiation. An emerging project aims to elucidate a novel pluripotency signalling network centering upon the Rnf12 E3 ubiquitin ligase.