A 2026 crick phd project with vivian li. Project background and description adult stem cells contribute to tissue homeostasis, regeneration upon damage and tumourigenesis when deregulated. Understanding the mechanistic control of stem cell maintenance is fundamental to human diseases and regeneration. Our lab use intestine as a model to study the regulation of stem cell lineage commitment, tumorigenesis and tissue regeneration (www.crick.ac.uk/vivian-li). Intestinal stem cell (isc) has been well characterised in the past since the identification of the stem cell marker lgr5. It is known that iscs reside at the crypt bottom where wnt signalling pathway is active. We have previously uncovered key transcriptional players regulating isc differentiation and lineage specification between absorptive and secretory fate at the progenitor cells, a process regulated by notch signalling. Our recent findings further showed that intestinal epithelial cells can be reprogrammed by ectopic expression of transcription factors or upon drug treatment. This project aims to study the control of cell state re-wiring in the intestinal epithelium (under homeostasis and injury) using organoids and transgenic mice. Intestinal organoids, also called “mini-guts”, are powerful research tools that allow us to model human organs and diseases in a dish. We will generate reporter lines to label different cell states of interest. Crispr screen will be performed in the organoids to uncover novel regulators of cell state re-wiring in the intestinal epithelium. The results generated will advance our understanding of the regulation of cellular plasticity and re-wiring in intestinal epithelium, which will shed light on stem cell homeostasis, regeneration and tumourigenesis. Candidate background we seek a highly talented and motivated phd candidate in the area of stem cell biology or developmental biology with experience in cellular plasticity and re-wiring to join dr. Vivian li’s lab at the crick. The successful candidate is likely to be an ambitious, focused, and productive individual with a desire to work in a congenial, dynamic, and collaborative research environment. Good organisational, analytical, and communication skills are essential. Candidate with experience in organoid culture, crispr/cas9 gene editing (knockin and knockout), spatial transcriptomics and/or transgenic mice will be advantageous. References meran, l., baulies, a. and li, v.s.w. (2017) intestinal stem cell niche: the extracellular matrix and cellular components. Stem cells international 2017: 7970385. Pubmed abstract baulies, a., angelis, n. and li, v.s.w. (2020) hallmarks of intestinal stem cells. Development 147: dev182675. Pubmed abstract baulies, a., angelis, n., foglizzo, v., danielsen, e.t., patel, h., novellasdemunt, l.,.. Li, v.s.w. (2020) the transcription co-repressors mtg8 and mtg16 regulate exit of intestinal stem cells from their niche and differentiation into enterocyte vs secretory lineages. Gastroenterology 159: 1328-1341.e1323. Pubmed abstract angelis, n., baulies, a., hubl, f., kucharska, a., kelly, g., llorian, m.,.. Li, v.s.w. (2024) loss of arid3a perturbs intestinal epithelial proliferation-differentiation ratio and regeneration. Journal of experimental medicine 221: e20232279. Pubmed abstract baulies, a., moncho-amor, v., drago-garcia, d., kucharska, a., chakravarty, p., moreno-valladares, m.,.. Li, v.s.w. (2024) preprint: sox2 drives fetal reprogramming and reversible dormancy in colorectal cancer. Available at: biorxiv. https://doi.org/10.1101/2024.09.11.612412 j-18808-ljbffr