Roel van DrielGroup leader Roel van Driel

tel.: 020-5255150
e-mail: r.vandriel@uva.nl

The in vivo choreography of a mammalian chromatin-associated process

This project aims at a comprehensive and quantitative understanding of the choreography of proteins and enzymatic processes involved in mammalian nucleotide excision DNA repair (NER). Methods have been developed and systematically implemented for the in vivo measurements of assembly rates and dissociation rates of essentially all NER-related proteins. In a collaborative program with the group of Thomas Höfer (DKFZ, Heidelberg, Germany) a all data have been integrated in a comprehensive quantitative and predictive mathematical model. Results give deep insight into the dynamics of the NER process. This insight can be extrapolated to other chromatin-associated processes, including transcription initiation.
Results show, among others, that chromatin-associated complexes at the one hand can be highly stabel, i.e. persist for hours, whereas at the same time individual proteins exchange at the seconds time scale between the bound and the nucleoplasmic state.
Presently, we are extending these analyses to the in vivo assembly of transcription initiation complexes

collaborators
Martijn Luijsterburg
Mattias Irving

previous collaborators
Martijn Moné

cooperations
Wim Vermeulen, Adriaan Houtsmuller and Jan Hoeijmakers, Erasmus University Rotterdam, Rotterdam, the Netherlands
Leon Mullenders, Leiden University, Leiden, the Netherlands
Thomas Höfer, DKFZ, Heidelberg, Germany

funding
National Medical Research Council ZonMW

recent publications

  • Luijsterburg, M.S., J. Goedhart, J. Moser, H. Kool, B. Geverts, A.B. Houtsmuller, L.H. Mullenders, W. Vermeulen, and R. van Driel. 2007. Dynamic in vivo interaction of DDB2 E3 ubiquitin ligase with UV-damaged DNA is independent of damage-recognition protein XPC. J Cell Sci. 120:2706-16.
  • Zotter, A., M.S. Luijsterburg, D.O. Warmerdam, S. Ibrahim, A. Nigg, W.A. van Cappellen, J.H. Hoeijmakers, R. van Driel, W. Vermeulen, and A.B. Houtsmuller. 2006. Recruitment of the nucleotide excision repair endonuclease XPG to sites of UV-induced dna damage depends on functional TFIIH. Mol Cell Biol. 26:8868-79.

Large-scale folding of the chromatin fibre in the interphase nucleus

Dynamic chromatin folding at the kb to Mb length scale is a key element in the regulation of gene expression in higher eukaryotes. Although there is a large body of observations concerning in situ chromatin folding in the literature, underlying principle are not understood.
In this project we systematically establish the relative volume, shape and nuclear radial position of gene-dense highly expressed genomic regions and regions that are gene-sparse and lowly expressed on the q-arms of chromosomes 1 and 11 in six different human cell lines. Results reveal a systematic difference in chromatin structure between the two functionally domains. The gene-poor subchromosomal domains are: (i) more roundish, (ii) more compact and (iii) located more closely near the nuclear envelope, than the gene-dense domains. These differences are the same in all six cell lines that have been analysed and therefore are independent from gene expression patterns.
In parallel we have systematically analysed the relationship between the genomic distance between two points on the linear genome and their physical distance in 3D in the G1 interphase nucleus. Results have been interpreted in terms of polymer models in close cooperation with the group of Dr Heermann (University Heidelberg).

collaborators
vacancy for a postdoc (3 years)

previous collaborators
Julio Mateos-Langerak
Sandra Goetze

cooperations
Rogier Versteeg and Hinco Gierman, AMC, Amsterdam, the Netherlands
Dieter Heermann and Manfred Bohn, Inst. Theoretical Physics, Univ. of Heidelberg, Heidelberg, Gemany

funding
FOM program 'Physics of the Genome': postdoc, 3 years
FP6 STREP '3D genome'

recent publications

  • Goetze, S., J. Mateos-Langerak, H.J. Gierman, W. de Leeuw, O. Giromus, M.H. Indemans, J. Koster, V. Ondrej, R. Versteeg, and R. van Driel. 2007. The three-dimensional structure of human interphase chromosomes is related to the transcriptome map. Mol Cell Biol. 27:4475-87.
  • Goetze, S., J. Mateos-Langerak, and R. van Driel. 2007. Three-dimensional genome organization in interphase and its relation to genome function. Semin Cell Dev Biol. 18:707-14.
  • Bohn, M., D. W. Heermann, et al. (2007). "Random loop model for long polymers." Phys Rev E Stat Nonlin Soft Matter Phys 76: 051805.

System properties of gene networks

Genomes of higher eukaryotes contain tens of thousands of genes that code for proteins and RNA molecules. Gene regulation is carried out by a hierarchical system involving at least three levels of organisation: (i) at the gene level via promoters and enhancers, (ii) the level of gene clusters involving epigenetic mechanisms, and (probably) (iii) the level of compartmentalisation of the cell nucleus. Despite extensive genome-wide analyses of gene expression patterns, it is still fully unclear how cells/organisms are able to switch on and off the correct genes at the correct time and at the correct place in the body. Probably, gene expression patterns are hard-wired in the structure of eukaryotic genomes. In part, this is via a network of transcription factors (TFs, 2,500 TF coding genes in the human genome) that regulate expression of the genes coding for these proteins.
In this project we intend to explore ideas how orchestration is achieved and translate such notions into predictive models, which subsequently can be falsified experimentally. The project builds on the vast amount of data that already is available in numerous databases about genome organisation, gene structure and gene expression.

collaborators
Jana Rudolf

cooperations
Frank Bruggeman, NISB, Amsterdam, the Netherlands

funding
University of Amsterdam

recent publications

  • Bruggeman, F.J., I. Oancea, and R. van Driel. 2008. Exploring the behavior of small eukaryotic gene networks. J Theor Biol. 252:482-487.

Publications 2000 – 2008

  • Bohn, M., D. W. Heermann, et al. (2007). "Random loop model for long polymers." Phys Rev E Stat Nonlin Soft Matter Phys 76(5 Pt 1): 051805.
  • Bruggeman, F. J., I. Oancea, et al. (2008). "Exploring the behavior of small eukaryotic gene networks." J Theor Biol 252(3): 482-487.
  • Cremazy, F. G., E. M. Manders, et al. (2005). "Imaging in situ protein-DNA interactions in the cell nucleus using FRET-FLIM." Exp Cell Res 309(2): 390-6.
  • De Leeuw, W., R. Van Liere, et al. (2000). "Visualization of Time Dependent Confocal Microscopy Data." Proceedings IEEE Visualization 2000: 473-476.
  • de Vries, A. H., B. E. Krenn, et al. (2005). "Micro magnetic tweezers for nanomanipulation inside live cells." Biophys J 88(3): 2137-44.
  • de Vries, A. H., B. E. Krenn, et al. (2007). "Direct observation of nanomechanical properties of chromatin in living cells." Nano Lett 7(5): 1424-7.
  • De Vries, A. H. B., S. J. Kanger, et al. (2004). "Patterned electroplating of micrometer scale magnetic structures on glass substrates." J. Microelectromechanical systems 13(3): 391-395.
  • Fakan, S. and R. Van Driel (2004). "Where do we go in the nucleus?" Biol Cell 96(8): 553-554.
  • Fakan, S. and R. van Driel (2007). "The perichromatin region: a functional compartment in the nucleus that determines large-scale chromatin folding." Semin Cell Dev Biol 18(5): 676-81.
  • Gierman, H. J., M. H. Indemans, et al. (2007). "Domain-wide regulation of gene expression in the human genome." Genome Res 17(9): 1286-95.
  • Gladilin, E., S. Goetze, et al. (2006). "Topological analysis of 3D cell nuclei using finite element template-based spherical mapping." Proceedings SPIE 6144: 1557-1566.
  • Gladilin, E., S. Goetze, et al. (2007). "Stochastical analysis of finite point sampling of 3D chromatin fiber in interphase cell nuclei." Proc. of BIRD: 104-118.
  • Goetze, S., J. Mateos-Langerak, et al. (2007). "The three-dimensional structure of human interphase chromosomes is related to the transcriptome map." Mol Cell Biol 27(12): 4475-87.
  • Goetze, S., J. Mateos-Langerak, et al. (2007). "Three-dimensional genome organization in interphase and its relation to genome function." Semin Cell Dev Biol 18(5): 707-14.
  • Greil, F., I. Van Der Kraan, et al. (2003). "Distinct HP1 and Su(var)3-9) complexes bind to sets of developmentally co-expressed genes depending on chromosomal location." Genes and Development 17: 2825-38.
  • Kanger, J. S., V. Subramaniam, et al. (2008). "Intracellular manipulation of chromatin using magnetic nanoparticles." Chromosome Res 16(3): 511-22.
  • Luijsterburg, M. S., J. Goedhart, et al. (2007). "Dynamic in vivo interaction of DDB2 E3 ubiquitin ligase with UV-damaged DNA is independent of damage-recognition protein XPC." J Cell Sci 120(Pt 15): 2706-16.
  • Mateos-Langerak, J., M. C. Brink, et al. (2007). "Pericentromeric heterochromatin domains are maintained without accumulation of HP1." Mol Biol Cell 18(4): 1464-71.
  • Mateos-Langerak, J., S. Goetze, et al. (2007). "Nuclear architecture: is it important for genome function and can we prove it?" J. Cell. Biochem.
  • Mone, M. J., T. Bernas, et al. (2004). "In vivo dynamics of chromatin-associated complex formation in mammalian nucleotide excision repair." Proc Natl Acad Sci U S A 101(45): 15933-7.
  • Oacea, I., R. Van Driel, et al. (2007). "Exploring the behavior of small eukaryotic gene clusters." J. Theor. Biol.

in preparation.

  • Politi, A., M. J. Mone, et al. (2005). "Mathematical Modeling of Nucleotide Excision Repair Reveals Efficiency of Sequential Assembly Strategies." Mol Cell 19(5): 679-690.
  • Politz, J., R. van Driel, et al. (2003). "From linear genome sequence to three-dimensional organization of the cell nucleus." Genome Biol 4(3): 310.
  • Post, L. J., M. Roos, et al. (2007). "A semantic web approach applied to integrative bioinformatics experimentation: a biological use case with genomics data." Bioinformatics 23(22): 3080-7.
  • Tessadori, F., M. C. Chupeau, et al. (2007). "Large-scale dissociation and sequential reassembly of pericentric heterochromatin in dedifferentiated Arabidopsis cells." J Cell Sci 120(Pt 7): 1200-8.
  • Tessadori, F., R. K. Schulkes, et al. (2007). "Light-regulated large-scale reorganization of chromatin during the floral transition in Arabidopsis." Plant J 50(5): 848-57.
  • van der Vlag, J., J. L. den Blaauwen, et al. (2000). "Transcriptional repression mediated by polycomb group proteins and other chromatin-associated repressors is selectively blocked by insulators." Journal of Biological Chemistry 275(1): 697-704.
  • Van Driel, R. (2001). "Kun je Leven uitrekenen?" Kanker 25(2): 22-22.
  • Van Driel, R. (2002). Method for the detection of mammalian carcinomas. Netherlands.
  • van Driel, R. (2007). "Chromatin is wonderful stuff." Semin Cell Dev Biol.
  • Van Driel, R., P. F. Fransz, et al. (2003). "The eukaryotic genome: a system regulated at different hierarchical levels." Journal of Cell Science 116: 4067-4075.
  • Verschure, P. J., I. van der Kraan, et al. (2005). "In vivo HP1 targeting causes large-scale chromatin condensation and enhanced histone lysine methylation." Mol Cell Biol 25(11): 4552-64.
  • Verschure, P. J., I. Van Der Kraan, et al. (2002). "Large-scale chromatin organization and the localization of proteins involved in gene expression in human cells." J Histochem Cytochem 50(10): 1303-12.
  • Visser, A. E., Van Driel, R. and Verschure, P.J. (2004). Functional organization of chromosomes in the interphase nucleus. Visions of the nucleus. P. Hemmerich, Diekmann, S. Stevenson Ranch, CA, USA, American Scientific Publishers.
  • Volker, M., M. J. Mone, et al. (2001). "Sequential assembly of the nucleotide excision repair factors in vivo." Mol Cell 8(1): 213-24.
  • Yang, S., S. Goetze, et al. (2007). "Variability of the large-scale structure of interphase chromatin fiber based based on statistical shape theory."
  • Zotter, A., M. S. Luijsterburg, et al. (2006). "Recruitment of the nucleotide excision repair endonuclease XPG to sites of UV-induced dna damage depends on functional TFIIH." Mol Cell Biol 26(23): 8868-79.