Modifications of collagen and chromatin in ECM-related disease

The extracellular matrix (EM) is essential to many biological functions, and is tightly regulated from the transcriptional level to the post-translational level. When this balance is disturbed, several ECM-related diseases can arise. Fibroproliferative pathologies, such as tissue fibrosis and solid tumors, are characterized by excessive production of the ECM protein collagen type I by myofibroblasts. Additionally, in irreversible forms of fibrosis, collagen type I contains extensive pyridinoline cross-links which essentially prevent the collagen fibrils from being degraded, thereby hampering subsequent tissue regeneration. Fibroproliferative pathologies pose an enormous burden on health-care systems worldwide, and urge the development of effective therapeutic strategies. The aim of this thesis was to provide a better understanding of the development of fibroproliferative pathologies by addressing the molecular processes underlying myofibroblast differentiation, collagen biosynthesis and collagen cross-linking. We dissected the transcriptional and post-translational processes needed to generate the pyridinoline cross-linking enzyme lysyl hydroxylase 2. Furthermore, we identified several chromatin-modifying enzymes that influence the transcriptional regulation of genes involved in various profibrotic processes. Finally, we developed innovative biotechnological tools that were successfully exploited to interfere with the transcriptional activity of disease-related genes by modulation of their epigenome. The findings discussed in this thesis not only provide a better understanding of fibrotic processes in general, but also offer several novel avenues that could aid tremendously to overcome these ECM-related diseases.

Dissertation: http://hdl.handle.net/11370/4178e6ed-a069-494d-a2ac-a215fcbdaa10