Head: prof dr Annemieke Smet
The mucin isoform landscape in barrier-related diseases
Loss of mucosal barrier integrity is a significant contributor in the pathophysiology of mucosal inflammatory/infectious diseases, but the role of transmembrane mucins, as epithelial signalling receptors mediating barrier dysfunction, is poorly understood. Upon inflammation, aberrantly expressed transmembrane mucins are likely to be the first point of contact between host tissue and the microbiota that penetrate the defective mucus layer and co-induce barrier dysfunction. Furthermore, the presence of genetic differences in mucin genes can give rise to a large repertoire of structurally diverse mucin mRNA isoforms via alternative splicing. While most isoforms encode similar biological functions, other have the potential to alter protein function resulting in progression towards disease. Currently, the mucin mRNA isoforms implicated in mucosal barrier dysfunction, is a scientific field to discover.
We recently showed that the transmembrane MUC1 and MUC13 mucins are involved in GI barrier dysfunction upon inflammation. Using a novel long-read RNA sequencing approach, we also discovered a higher number of novel and unique MUC1 and MUC13 mRNA isoforms in inflamed colonic tissue compared to healthy tissue which explains the increased MUC1 and MUC13 expression seen in IBD patients. Therefore, our research focuses on 1) the discovery of the MUC1 and MUC13 isoform landscape, mediating mucosal barrier dysfunction in inflammatory bowel diseases (IBD), gastrointestinal cancers (GC and CRC) and respiratory tract infections (RVS, COVID-19) as well as 2) the different levels of regulation (i.e. microbial and inflammatory triggers) mediating alternative mucin splicing. We implement an unconventional approach encompassing a broadly applicable framework with next-generation sequencing tools, human sample collections and translational models. This work could lead to a new paradigm shift greatly advancing novel applications for disease follow-up and pathology-specific targeting.
Technology Transfer Potential
Mucins and isoforms thereof in diseases characterized by barrier dysfunction: WO2021013479
Key Publications
Breugelmans T, Arras W, Boen LE, Borms E, Kamperdijk L, de Man J, van de Vijver E, van Gils A, De Winter BY, Moes N, Smet A. Aberrant mucin expression profiles associate with pediatric inflammatory bowel disease presentation and activity. Inflamm Bowel Dis 2022 Oct 14:izac217.doi:10.1093/ibd/izac217.
Breugelmans T, Oosterlinck B, Arras W, Ceuleers H, De Man J, Hold G, De Winter BY, Smet A. The role of mucins in gastrointestinal barrier function in health and disease. Lancet Gastroenterology and Hepatology, 2022, 7(5):455-471.
Smet A, Breugelmans T, Michiels J, Lamote K, Arras W, De Man JG, Heyndrickx L, Hauner A, Huizing M, Malhotra-Kumar S, Lammens M, Hotterbeekx A, Kumar-Singh S, Verstraeten A, Loeys B, Verhoeven V, Jacobs R, Dams K, Coenen S, Ariën KK, Jorens PG, De Winter BY. A dynamic mucin mRNA signature associates with COVID-19 disease presentation and severity. JCI Insight, 2021, 6(19): e151777.
Breugelmans T, Van Spaendonk H, De Man JG, De Schepper HU, Jauregui-Amezaga A, Macken E, Linden SK, Pintelon I, Timmermans JP, De Winter BY, Smet A. In depth study of transmembrane mucins in association with intestinal barrier dysfunction during the course of T cell transfer and DSS-induced colitis. J Crohn’s & colitis, 2020, 14(7): 974-994.
Staff, PhDs & Projects
PhD Tom Breugelmans
Role of MUC-13 signalling on epithelial barrier disruption in gastrointestinal disorders
PhD Helena Berlamont
Gastric Helicobacter infection and its role in neurodegenerative disorders
PhD Baptiste Oosterlinck
Interaction between MUC13 signalling and mucosal microbiota in the development of gastric cancer
PhD Wout Arras
A mucine-isoform based biomarker test for improved detection and treatment of IBD and gastrointestinal cancer