Molecular epigenetic mechanisms in development, cancer and metabolism

Gene-environment interactions - molecular epigenetic mechanisms underlying embryogenesis, oncogenesis and metabolic responses. Central to our studies are the molecular links between cell signalling and chromatin structure modulation. Chromatin structure remodeling is a vital aspect of numerous important DNA-templated processes (i.a. transcription, DNA replication, DNA repair, imprinting, X-inactivation) and hence of development and homeostasis. Disruption of chromatin remodelling is at the basis of abnormal development, tumorigenesis and the metabolic syndrome In contrast to (congenic, acquired) genetic abnormalities, abnormal epigenetic control may be responsive to and corrected by changing the cells’ microenvironment (nutrients, oxygen, drugs). Clinical application of epigenetic therapy requires detailed understanding of underlying molecular mechanisms.

Signalling to chromatin; novel interactors of Polycomb Group proteins
The Polycomb Group of regulator complexes play pivotal roles in many chromatin-based processes. Our team produced one of the first molecular connections between cell signalling and chromatin remodelling by Polycomb Group (PcG) proteins: activation of the canonical MAPK pathways activates downstream kinases called MAPKAP-kinases, which we identified as PcG-kinases. We showed MK3 is an integral member of PcG complexes and identified a role for MK3 in a negative feedback mechanism that re-establishes PcG-mediated gene repression. Post-translational modifications control protein interactions, activity and stability. We discovered that MK3 and PcG are functionally connected in proliferative capacity. As MK3 is often lost or over-active in tumors, our findings have a direct bearing on our understanding of abnormal differentiation and proliferation in cancer. Current studies focus on post-translational modification of PcG proteins and their molecular consequence and biological relevance (development, cancer, metabolic responses). These studies are carried out with international collaborators (F Peronnet, Paris, FR; UR Rapp, Münich, GE) and include state-of-the-art omics and molecular genetics approaches.

Tissue regeneration; gene-environment interactions in chondrogenesis
The Molecular Epigenetics (J.W. Voncken) and Orthopaedic Surgery and Research (LW vanRhijn, TJM Welting) teams have jointly identified novel molecular epigenetic connections in the context of early responses in chondrogenic differentiation. We identified an important role for immediate early genes EGR1 and PcG proteins in coordinating proliferation and differentiation during the initial phases of chondrogenic commitment. Our current efforts have focussed on the intervertebral disc (IVD). Disc degeneration poses a substantial socio-economic burden in developed countries and for which no effective therapy is available. To develop cell replacement and tissue regeneration therapy, much improved understanding of cell ontogeny and their molecular interactions with the micro-environment in healthy and diseased tissue is required. We have established unique novel cell lines representing distinct subpopulations in the IVD. These cell lines have yielded novel biomarkers that differ among subpopulations within the central nucleus pulposus and the surrounding annulus fibrosus, and are currently being studied to ultimately improve regeneration strategies.

Microenvironment, epigenetics and stem cells in development and cancer
Epigenetic regulation mediates adaptation to changes in the micro-environment and constitutes a major underlying mechanism in development, maintenance of cellular diversity, phenotypic plasticity and homeostasis. Cancer cells in solid tumors are often exposed to fluctuating oxygen tension resulting from inadequate blood supply due to poorly developed vasculature. Transcriptional changes in hypoxic cancer cells enable cancer cells to survive and adapt to the hypoxic environment. Repeated oxygen deprivation and reoxygenation is thought to promote tumor stem cell properties, metastasis, and poor patient prognosis. The Molecular Genetics (J.W. Voncken) and Tumor Oncology group (B.G. Wouters; Toronto, Canada) have recently discovered that hypoxia exposure increases global histone-trimethylation and induces a bivalent epigenetic state on numerous key regulatory genes. Current studies focus on the functional consequences thereof for normal and abnormal growth and development.