Functions of the ERK5 signalling pathway in Pluripotent Stem Cells

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Pluripotent Embryonic Stem Cells (ESCs) have the capacity to self-renew and differentiate into all specialized cell types in the adult body. ESC decision-making is tightly controlled by cellular signalling networks, which our lab seeks to unravel and exploit to elaborate novel ESC-based cell replacement strategies (Fernandez-Alonso et al, 2017). In a recent small molecule kinase inhibitor screen, we uncovered a critical function for the ERK5 signalling pathway in controlling ESC pluripotency. Using inhibitor engineering and CRISPR/Cas9 genome editing, we find, excitingly, that ERK5 modulates transition between "naïve" and "primed" pluripotent ESC states (Williams et al, 2016). We are now applying cutting-edge quantitative systems biology technologies to unravel molecular functions of ERK5 in ESCs. As ERK5 uniquely contains a kinase domain and a putative transcriptional domain, a key aim is to gene whose expression is regulated by ERK5. To this end, we will define the role of ERK5 in regulating ESC gene expression and proteome dynamics using RNA-SEQ transcriptomics and total proteomic profiling mass-spectrometry. This uncovers a new function for the ERK5 signalling pathway in regulating expression of early embryonic genes associated with reprogramming to naïve pluripotency and attaining totipotency, an embryonic state that is developmentally unrestricted. Therefore, we to identify molecular mechanisms that activate ERK5 signalling in ESCs, and exploit this information to reprogram somatic cells to naïve pluripotency and potentially totipotency. Ultimately, this knowledge will provide new avenues towards reprogramming cells more efficiently and towards totipotency.Key Words: Embryonic Stem Cell, Regenerative Medicine, Signal Transduction, Protein KinaseQuantitative Skills: Quantitative Mass-Spectrometry, TranscriptomicsWhole Organism Physiology: Systems Biology, Stem CellsQuestions:1. Explain interdisciplinary interface: This project interfaces quantitative analysis with systems biology and whole organism physiology by employing quantitative mass-spectrometry and transcriptomic profiling to address systems biology question in stem cells2. Does project require significant amount of quantitative skills? YES 3. Does project require significant amount of whole organism physiology skills? YES