Glycosaminoglycans (GAGs) are polysaccharides present on the surface of most cells and in the extracellular matrix (ECM) of all tissues that influence how cells interact with their pericellular environment. GAG activities are mediated via the binding of protein ligands (growth factors, cytokines, matrix components etc.) to motifs encoded within the GAG chains. The chains are constructed through the action of multiple enzymes which themselves are under transcriptional, metabolic, and epigenetic control.

 

Currently, we lack a thorough understanding of how the functional activity of a GAG links to its structure and, critically, how GAG structure is controlled by cells. This prevents the harnessing of GAGs for multiple bioscience applications: it is currently impossible to predict changes in GAG motifs/activity from transcriptomic datasets, or to select which enzymes should be combined to synthesise a GAG with a specific function.

 

We have assembled an interdisciplinary team with complementary approaches, including the use of 3D in vitro models of development (gastruloids) to provide material for coordinated analyses, creating an interconnected web of information that we will then use to generate and test hypotheses. Transcriptomic and proteomic analyses linked to detailed structural and spatial analysis of GAGs will allow us to build and then refine models of how the biosynthetic machinery creates particular GAG structures, allowing us to generate and apply a novel toolbox of GAG-binding probes. Coordinating this information with defined developmental stages and responses to known GAG-dependent ligands (e.g., BMP, FGF family members etc.) will directly link structure to function. To test emergent hypotheses, we will use gene editing to target key regulatory hotspots in the 3D gastruloid models, allowing the refinement of our understanding of the critical factors controlling GAG structure and function and how this maps onto molecular and biological function.