Seminar

Contextualized Functions of Glycans in Human Tissue Formation

Prof. Hans H. Wandall

More than 200 different types of post-translational modifications (PTMs) finetune the structure and function of proteins in human tissue. The most diverse and abundant subtype of PTM is believed to be glycosylation. Glycans exhibit a large structural diversity with cell-type specificities that underlie defined biological functions. However, our functional understanding of the glycome is limited, partially due to the lack of simple model systems that allow for open-ended, unbiased screens of glycan function in human tissues. We here present the first human organotypic platform to systematically interrogate glycan functions in tissue formation. Using CRISPR-Cas9 and a 3D organotypic model of human skin, we have generated a human tissue library with truncation of the key glycan structures, thus providing a platform contextualized to a human setting with broad discovery potential. The library demonstrates distinct phenotypes associated with loss of individual glycosylation pathways, including the effect of complex N-glycans on wound healing, O-GalNAc glycans on cell-cell adhesion, differential roles for O-Fucose and O-Glucose glycosylation in NOTCH signaling and glycosphingolipids in EGF signaling and skin barrier formation. The platform can help define the roles of the glycome in epithelial homeostasis, epithelial transformation, cell-cell and cell-matrix adhesion, signaling and host pathogen interactions, enabling glycobiology to move beyond the constrains of 2D cell culture assays, printed glycan arrays, and animal models.