Research Interest
Role of Polycomb-Group genes in transcriptional repression, stem cell fate and tumorigenesis
Our lab has a long-standing interest in epigenetic gene regulation dictated by chromatin modifications. We study the mechanism of stable inherited transcriptional repression by Polycomb-group (Pc-G) protein complexes, and the effects of deregulation of Pc-G genes on development, cell cycle control, cancer formation and stem cell maintenance.
Currently, the lab uses three model organisms, namely mouse (Mus musculus), fly (Drosophila melanogaster) and zebrafish (Danio rerio).
Retroviral insertional mutagenesis & Cancer genomics
Slow transforming retroviruses, such as the Moloney murine leukemia virus (M-MuLV), induce tumors upon infection of a host after a relatively long latency period. These retroviruses can transform the infected host cells through the accidental insertion of their proviruses into the host genome in the vicinity of genes that can confer growth advantages to cells. This means that the proviral insertions found in tumors induced by retroviral insertional mutagenesis mark genes contributing to the tumorigenic process. Since cancer is a complex multistep process, the proviral insertions in one clone of tumor cells also represent oncogenic events that co-operate in tumorigenesis. Novel advances, such as the launch of the complete mouse genome, high-throughput isolation of proviral flanking sequences, new dedicated bioinformatic tools and genetically modified animals have revolutionized proviral tagging into an elegant and efficient approach to identify signaling pathways that collaborate in cancer. This project is executed together with Anton Berns in our department. We have made much progress in the last year and identified over 600 putative oncogenes and tumor suppressor genes. This project is yielding an unexpected wealth of information on haploinsufficient tumor suppressor genes and specific cooperation of oncogenes. It also appears to validate and complement large-scale sequencing efforts of cancer genomes.
Key publications
Jacobs, J. J. L., Kieboom, K., Marino, S., DePinho, R. A. and van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the INK4a locus. Nature 397, 1999, 164-168.
Jacobs, J. J. L., Scheijen, B., Voncken, J. W., Kieboom, K., Berns, A. and van Lohuizen, M. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev., 1999, 13, 2678-2690.
Voncken, J. W., Schweizer, D., Aagaard, L., Sattler, L., Jantsch, M. F. and van Lohuizen, M. Chromatin-association of the Polycomb group protein BMI1 is cell cycle regulated and correlates with its phosphorylation status. J. Cell Sci., 1999, 112, 4627-4639.
Jacobs, J. J. L, Keblusek, P., Robanus-Maandag, E., Kristel, P., Lingbeek, M., Nederlof, P. M., van Welsem, T., van de Vijver, M. J., Koh, E. Y., Daley, G. Q., and van Lohuizen, M. Senescence bypass screen identifies TBX2, which represses Cdkn2A (p19ARF) and is amplified in a subset of human breast cancers. Nature Genet. 2000, 26, 291-299.
Akasaka, T., van Lohuizen, M., van der Lugt, N., Mitzutani-Koseki, Y., Kanno, M., Taniguchi, M., Vidal, M., Alkema, M., Berns, A., and Koseki, H. Mice doubly deficient for the Polycomb-group genes Mel18 and Bmi1 reveal functional redundancy and requirement for maintenance but not initiation of Hox gene expression. Development, 2001, 128, 1587-1597.
Brock, H. W. and van Lohuizen, M. The Polycomb-group-no longer an exlusive club? Curr. Opin. Genet. Dev., 2001, 11, 175-181
Jacobs, J.J.L. and van Lohuizen, M. Polycomb repression: from cellular memory to cellular proliferation and cancer. BBA Reviews in Cancer, 2002, 1602, 151-161.
Lingbeek M.E., Jacobs J.J.L. and Van Lohuizen, M. The T-box repressors TBX2 and TBX3 specifically regulate the tumor-suppressor p14ARF via a variant T-site in the initiator.
J Biol Chem. 2002, 277, 26120-26127.
Lund, A.H., Turner, G., Trubetskoy, A.,Verhoeven, E., Wientjens, E., Hulsman, D., Russell, R., DePinho, R.A., Lenz, J., and van Lohuizen, M. Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice. Nature Genet. 2002, 32, 160-165.
Voncken, J.W., Roelen, B.A.J., Roefs, M., de Vries, S., Verhoeven, M., Marino, S., Deschamps, J. and van Lohuizen, M. Rnf2 (Ring1b) Deficiency Causes Gastrulation Arrest and Cell Cycle Inhibition. Proc. Natl. Acad. Sci. USA 2003,100, 2468-2473.
More publications by Maarten van Lohuizen on PubMed
List of relevant websites
Centre for Biomedical Genetics
Cancer Genomics Centre www.cancergenomics.nl/
Stem Cells in Development and Disease (SCDD)http://www2.eur.nl/fgg/ch1/stemcells/
EPIGENOME NoE http://www.epigenome-noe.net/
Biographic sketch
Maarten van Lohuizen studied Biology at the University of Amsterdam and received his Ph.D. in 1992 (cum laude, supervisors Dr. A. Berns and Prof dr. P. Borst) from the same University. During his thesis work, he demonstrated the power of using retroviruses in genetic screens to identify cooperating oncogenes in cancer-predisposed mice.
After staying on for one year as a postdoc, he joined the group of Prof. Dr. Ira Herskowitz, University of California at San Francisco, USA, for his postdoctoral training. Here, he was involved in analysis of a novel cell cycle checkpoint mechanism and in studying regulation of the Yeast MAP-kinase signaling pathway. In 1995 he returned to The Netherlands Cancer Institute as an assistant professor in the division of Molecular Carcinogenesis, to take up studying his old favorite: mechanisms of epigenetic silencing by mammalian Polycomb-group protein complexes and their role in cancer, when deregulated. After his tenure in 2000, he joined the division of Molecular Genetics in 2001, of which he was appointed head of division in 2002. In addition, in 2001 he became a part time professor on the subject of regulation of Cell Cycle control and Oncogenesis at Utrecht University Medical School and was appointed as a member of the Centre for Biomedical Genetics in 2003 and as EMBO member in 2004. In 2007 he became part time professor at the University of Amsterdam Medical School (AMC) with the profile: Biology and epigenetic regulation of normal and cancer stem cells.
His group has made important contributions on the functional analysis of epigenetic gene silencing mechanisms by Polycomb-group protein complexes, which play crucial roles in controlling development and cell fate and when deregulated, contribute to cancer formation. Recently, his group has also developed high-throughput genome-wide genetic screens in cell-based assays and in cancer-prone mice (in collaboration with Prof. Dr. A. Berns and Prof. Dr. A. Bradley, The Sanger Center, UK) to identify new genes that contribute to cancer and classify them in functional groups/signaling pathways. By using the DamID technique, his group has recently comprehensively mapped all Polycomb target genes in the Drosophila genome (in collaboration with the group of Bas van Steensel. In addition, his group has recently demonstrated a crucial role for Bmi1/Pc-G protein complexes in maintaining hemapoietic, neuronal, breast epithelial and embryonal stem cell fate and has implicated the Sonic Hedgehog (Shh) morphogen as a regulator of Bmi1 expression in neuronal precursor cells. Unraveling the role of Bmi1/Pc-G in stem cell fate versus differentiation decisions and the consequence of this for cancer (stem) cell biology is currently a major focus of his group.
Coworkers
Bart Westerman PhD Post-doc
Anke Sparmann PhD Post-doc
Bas Tolhuis PhD Post-doc
Karim Nacerddine PhD Post-doc
Jean-Bernard Beaudry PhD Post-doc
Jaap Kool PhD Post-doc
Panthea Taghavi MSc Graduate student
Danielle Hulsman Technical staff
Ellen Tanger Technical staff
Marleen Blom Technical staff
Els Verhoeven Technical staff
An independent group working with Zebrafish shares the lab:
Anna Pavlina Haramis PhD Research Associate
Yme van der Velden MSc Graduate student
» Vacancies
Post docs interested in our work please contact Dr. van Lohuizen (m.v.lohuizen@nki.nl)