PADIngton - The role of protein citrullination in the regulation of cell fate

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This project aims to characterize a novel mechanism in the regulation of cell fate and delineate the underlying molecular events. The discovery that somatic cells can be reprogrammed to a pluripotent state and instructed to differentiate into various cell types has revolutionized regenerative medicine. However, we lack rational approaches to enhance reprogramming efficiency. Understanding the signal transduction mechanisms that regulate the establishment of pluripotency promises to offer interventions that will increase reprogramming efficiency and allow for increasingly specific intervention towards regenerative medicine.The host lab has pioneered the study of peptidylarginine deiminase (PADI) enzymes in stem cell biology, showing that the chromatin modifier PADI4 regulates the establishment of pluripotency in cell reprogramming and embryo development. This project will investigate how protein citrullination allows the integration of cell signalling inputs and how this impacts cell identity transitions through the modulation of chromatin state and gene expression. I will combine my research background with the world-class expertise present in the host lab and wider institute to address the above questions, using a combination of cell biological, cell signalling and genetic approaches as well as imaging and single-cell transcriptomics. I will assess the physiological relevance of my findings in tissue regeneration using organoid cultures and in vivo models. This project has the potential to transform our understanding of the reprogramming process and identify approaches to promote tissue regeneration while providing me with excellent training and allowing me to grow as an independent scientist.