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.
(selection; *shared authorships)
Spaapen F*, Akker GGH van den*, Caron, MMJ, Prickaerts P, Rofel C, Dahlmans VEH, Surtel DAM, Paulis Y, Schweizer F, Welting TJM, Eijssen LM, Voncken JW. The immediate early gene product EGR1 and Polycomb Group proteins interact in epigenetic programming during chondrogenesis. PLoS One 8 (2013) e58083.
Prickaerts P, Niessen HE, Mouchel-Vielh E, Dahlmans VE, van den Akker GG, Geijselaers C, Adriaens ME, Spaapen F, Takihara Y, Rapp UR, Peronnet F, Voncken JW. MK3 controls Polycomb target gene expression via negative feedback on ERK. BMC Epigen Chrom 5 (2012) 12.
Kubben N, Adriaens M, Meuleman W, Voncken JW, van Steensel B, Misteli T. Mapping of lamin A- and progerin-interacting genome regions. Chromosoma 121 (2012) 447-64.
Caron MM, Emans PJ, Surtel DA, Cremers A, Voncken JW, Welting TJ, van Rhijn LW. Activation of NF-κB/p65 facilitates early chondrogenic differentiation during endochondral ossification. PLoS One 7 (2012) e33467
Welting TJM, Caron MMJ, Emans PJ, Janssen MPF, Sanen K, Coolsen MME, Voss L, Surtel DAM, Cremers A, Voncken JW* and van Rhijn LW*. Inhibition of cyclooxygenase-2 impacts chondrocyte Hypertrophic differentiation during endochondral ossification. Eur Cells Mat 22 (2011) 420-37.
Kubben N*, Voncken JW*, Konings G, Houten S, Gijbels M, Erk A van, Schoonderwoerd K, Bosch B van den, Dahlmans V, Calis C, Wanders R, Misteli T, Pinto Y. Post-natal myogenic and adipogenic developmental defects and metabolic impairment upon loss of A-type lamins. Nucleus 2 (2011) 195-207.
Kubben N, Voncken JW, Misteli T. Mapping of protein- and chromatin-interactions at the nuclear lamina. Nucleus 1 (2010) 460-71.
Emans PJ, Rhijn LW van, Welting TJM, Cremers A, Wijnands N, Spaapen F, Voncken JW, Shastri P. Autologous Engineering of Cartilage. Proc Natl Acad Science 107 (2010) 3418-23.
Rouschop K, vandenBeucken T, Dubois T, Niessen HEC, Bussink J, Savelkouls K, Keulers T, Mujcic H, Landuyt W, Voncken JW, Lambin P, van der Kogel A, Koritzinsky M, Wouters B. The unfolded protein response protects cells during hypoxia through regulation of the autophagy genes LC3b and ATG5. J Clin Invest (2010) 120:127-41.
Niessen HEC, Demmers JA, and Voncken JW. Talking to Chromatin: post-translational Modulation of Polycomb Group Function. BMC Epigen Chrom (2009) 2:10 (Top 3 most accessed all time).
Borne van den SWM, Narula J, Voncken JW, Lijnen PM, Vervoort-Peters HTM, Dahlmans VEH, Smits JFM, Daemen MJAP, Blankesteijn WM. Defective intercellular adhesion complex in myocardium predisposes to infarct rupture in humans. J Am Coll Card (2008) 51: 2184-2192.
Voncken JW*, Niessen H*, Neufeld B, Kubben N, Holzer B, Dahlmans V, Rennefahrt U, Ludwig S, Rapp UR. MAPKAP kinase 3pK phosphorylates and regulates chromatin-association of the Polycomb-Group Protein Bmi1. J Biol Chem 280 (2005): 5178-87.
Van Berlo JH*, Voncken JW*, Kubben N, Broers JLV, Duisters R, van Leeuwen REW, Crijns HJGM, Ramaekers FCS, Hutchison CJ, Pinto YM. A-type lamins are essential for TGF-β1 induced PP2A to dephosphorylate transcription factors. Human Mol Genetics 14 (2005) 2839-2849.
Voncken JW, Roelen B, Roefs M, de Vries S, Marino, S, Deschamps J and van Lohuizen M. Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition. Proc Natl Acad Science 100 (2003) 2468-73.
Voncken JW, Schweizer D, Aagaard L, Sattler L, Jantsch MF, van Lohuizen M. Chromatin-association of the Polycomb group protein BMI1 is cell cycle-regulated and correlates with its phosphorylation status. J Cell Sci 112 (1999) 4627-4639.
Jacobs J*, Scheijen B*, Voncken JW, Kieboom K, Berns A, van Lohuizen M. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev 13 (1999) 2678-2690.
Voncken JW, Kaartinen V, Groffen J and Heisterkamp N. BCR-ABL associated leukemogenesis in bcr null mutant mice. Oncogene 16 (1998) 2029-2032.
Kaartinen V, Mononen I, Voncken JW, Noronski T, Gonzalez-Gomez I, Heisterkamp N and Groffen J. A mouse model for the human lysosomal disease aspartylglycosaminuria. Nature Medicine 2 (1996) 1375-1378.
Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N and Groffen J. Abnormal lung development and cleft palate: defects of epithelial-mesenchymal interaction in mice lacking TGF-ß3. Nature Genetics 11 (1995) 415-421.
Voncken JW, Van Schaick H, Kaartinen V, Landing, B, Pattengale PK, Deemer K, Coates T, Dorseuil, O, Bokoch, GM, Groffen J and Heisterkamp N. Increased neutrophil respiratory burst in bcr-null mutants. CELL 80 (1995) 719-728.
Voncken JW, Kaartinen V, Pattengale PK, Germeraad WTV, Groffen J and Heisterkamp N. BCR/ABL P210 and P190 cause distinct leukemia in transgenic mice. Blood 86 (1995) 4603-4611.
Voncken JW, Griffiths SD Greaves, MF Pattengale PK, Heisterkamp N and Groffen J. Restricted oncogenicity of BCR/ABL P190 in transgenic mice. Cancer Research 52 (1992) 4534-4539.
Voncken JW, Morris C, Pattengale PK, Dennert G, Kikly C, Groffen J and Heisterkamp N. Clonal development and karyotype evolution during leukemogenesis of BCR/ABL transgenic mice. Blood 79, 4 (1992) 1029-1036.
Willem Voncken, PhD
Vivian E.H. Dahlmans-van Leeuwen (senior expert technician), Peggy Prickaerts, PhD (postdoc; tumor epigenetics), Guus G.H. van den Akker MSc (PhD student; signalling and epigenetics in cartilage), Xiaoqing Zhu MSc (PhD student; epigenetics in metabolic responses), Jolien Vanhove MSc (PhD student, KU Leuven; iPSCs in hepatogenesis), Isabelle Schiffer MSc (PhD student, USC Los Angeles; leukemia research).
Past PhD students: Hanneke Niessen, PhD (molecular epigenetics), Frank Spaapen, PhD (molecular epigenetics), Pieter Emans, PhD (Orthop), Edwin Janssen, PhD (Orthop).
The team hosts local national and international undergraduate students.