Project ID CM-HD2023_02

ThemeCM-HD

Co Supervisor 1A FoDOCS, Centre for Stem Cells & Regenerative BiologyWebsite

Co Supervisor 1B FoLSM, Medical and Molecular GeneticsWebsite

Understanding the molecular mechanisms of stem cell regulation and tumour suppression using multi-omics

Adult stem cells drive organ regeneration and homeostasis, but their dysregulation can lead to tumourigenesis or organ failure. Regenerative medicine aims to replace functional cells without triggering uncontrolled proliferation. A barrier to translation is our inability to direct stem cells down appropriate commitment steps in a controlled manner.
Using mouse genetics, we generated mutants whereby YAP is overexpressed throughout the pituitary gland, a primary endocrine organ controlling fundamental physiological functions, We found that levels of YAP are critical for pituitary stem cell (PSC) activity, where low levels instigate PSC self-renewal without causing disease, but high levels lead to tumour formation and repression of differentiated cell fates. We carried out cutting-edge single nuclei multi-omics to profile the transcriptomes (snRNAseq) and chromatin accessibility (sn-ATACseq) of these pituitaries. These datasets allow establishment of the molecular mechanisms driving PSC self-renewal and the fine balance between normal expansion and tumourigenesis. We are particularly interested in exploring the role of environmental factors on stem cell pathway regulation, since recent data suggest that high fat diets can influence stem cell behaviour and the promotion of tumours.
Objectives:
1. Mine datasets to establish differences in chromatin state and gene expression in PSCs and committed cells between the activated and control tissues, at single cell resolution. Year1.
2. Identify novel drivers of stem cell behaviour, focusing on environmentally-responsive transcription factors and their role during normally physiology and disease. Years2/3.
3. Build and functionally test gene regulatory networks. Years2/3.

One representative publication from each co-supervisor:

• Lodge, EJ. et al. Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade (2019) Elife https://doi.org/10.7554/eLife.43996.001

• Scagliotti, V. et al. Dynamic expression of imprinted genes in the developing and postnatal pituitary gland. https://doi.org/10.3390/genes12040509