Cells send chemical signals to each other, and a pathway called WNT controls how stem cells turn into specific tissues like the gut, liver, and pancreas—but the molecular steps that translate these signals into gene activity remain poorly understood. This research addresses a fundamental gap: how the protein GSK3, part of the WNT signalling pathway, chemically modifies a DNA-regulating complex called CHD4-NuRD to switch genes on or off. Without this knowledge, scientists cannot fully explain how embryos form, how adult tissues regenerate, or why faulty WNT signalling drives many cancers. If successful, the project will map the precise molecular chain from a WNT signal at the cell surface to changes in gene expression inside the nucleus. This is fundamental science—it will not directly produce a drug or a diagnostic. But understanding the GSK3–CHD4 axis could eventually help researchers design therapies that correct misregulated WNT signalling in cancer or improve methods to grow replacement tissues from stem cells. Similar fundamental discoveries about signalling pathways have, in the past, underpinned targeted cancer treatments and regenerative medicine approaches now in clinical use.
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Lay abstract: 550 words In our body, cells communicate through chemical signals that allow them to respond to their environment and neighbouring cells. This signalling is essential for cell specialization and organ formation. Signals are transmitted through molecular steps to the DNA, where they control how genes are turned ON and OFF to instruct cell behaviour. "WNT”s are key signalling molecules that play essential roles in normal development by mediating communication between cells. WNT-signalling is used by many species to guide tissue formation during both embryonic development and adult tissues. Given its significance, it's not surprising that WNT-signalling is also one of the most frequently activated pathways in cancer. However, there is a fundamental gap in our knowledge about the molecular steps by which WNT signals control gene expression. Understanding these molecular steps is key to understand how tissues are formed and can also reveal how dysregulated WNT-signalling drives tumour formation. We’ve discovered that a key protein in the WNT signalling pathway, called GSK3, affects certain proteins involved in DNA regulation, known as the CHD4-NuRD complex. GSK3 controls this by tagging the CHD4-NuRD complex with a chemical modification called phosphorylation. This chemical modification changes how the CHD4-NuRD complex controls the expression of target genes. We have studied this mechanism in stem cells, which can specialize into any cell type in our body. We found that the GSK3-CHD4 pathway specifically controls how stem cells specialize into the endoderm lineage, which ultimately forms tissues like the gut, liver, and pancreas. These observations lead us to hypothesize that GSK3-CHD4 molecular axis plays an important role in stem cells. Thus, this research proposal aims to find out the molecular mechanisms by which the novel GSK3-CHD4-NuRD pathway regulates gene expression and cell identity in stem cells. Understanding these mechanisms is crucial for understanding normal development, tissue regeneration, and cancer, where GSK3/WNT signalling and CHD4-NuRD proteins play a key role. Firstly, we will use various methods to activate WNT-signalling and find out whether WNT signals directly influence the phosphorylation of CHD4-NuRD complex and whether this is specific to stem cells. These experiments will also give us a broad view of all the proteins that change their phosphorylation tag in response to WNT signals. Secondly, we will use advanced genomics methods to study how GSK3/WNT-signalling controls how CHD4-NuRD complex binds to DNA in stem cells and during endoderm specialization. Exploring this process is important to better understand how genes are silenced by the CHD4-NuRD complex. Lastly, we will look at other proteins that work with the CHD4-NuRD complex as stem cells mature and see how GSK3/WNT signalling affect these interactions. This will help us discover new proteins that are involved in specialization of stem cells into endoderm cells. This research will fill a major gap in our knowledge of the molecular mechanisms that regulate gene expression in response to GSK3/WNT-signalling, which is of huge relevance to our understanding of health and disease. Thisfundamental knowledge could also have implications for improving the treatment of disorders associated with faulty WNT-signalling.
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