BIOQUANT > Research Groups > Chromatin Networks > People > Dr. Nikolaus Kepper

Dr. Nikolaus Kepper

Research Interests

My work focuses on the modeling of the 30 nm chromatin fiber by computer simulations. Currently, the main goal is to analyze the effect of the nucleosome geometry and the nucleosome-nucleosome interactions on the fiber conformation. Based on model structures with atomic resolution a new coarse-grained model for the nucleosome geometry was implemented. The dependence of the chromatin fiber conformation on the spatial orientation of nucleosomes, the path of the linker DNA, and length of the linker DNA was systematically explored by Monte Carlo simulations. Two fiber types were analyzed in detail. They represent nucleosome chains without and with linker histones, respectively: two-start helices with crossed-linker DNA and interdigitated one-start helices with different nucleosome tilt angles. The crossed-linker conformation was derived from a tetranucleosome crystal structure that was extended into a fiber. At thermal equilibrium the fiber shape persisted but relaxed into a structure with a somewhat lower linear mass density of 3.1 ± 0.1 nucleosomes/11 nm fiber. Stable interdigitated fibers required local nucleosome tilt angles between 40° and 60°. For these configurations much higher mass densities of up to 8.0 ± 0.2 nucleosomes/11 nm were obtained. A model is proposed, in which the transition between a crossed-linker and interdigitated fiber is mediated by relatively small changes of the local nucleosome geometry. These were found to be in very good agreement with changes induced by linker histone H1 binding as predicted from the atomic model structures.

Scientific Background

2002 to mid 2005 PHD in the group of Prof. C. Cremer, division Applied Optics and Information Processing at the Kirchhoff-Institute for Physics, Ruprecht-Karls-Universität Heidelberg, topic: 'Brownian Dynamics simulations of whole cell nuclei to determine motion patterns of chromosomes and gene regions on the basis of the 1-Mbp SCD model'.
since mid 2005 post doctoral fellow in the group of Karsten Rippe, Research Group Genome Organization & Function at the DKFZ Heidelberg. topic: 'Models of chromtin organisation'
from 2009 on post doctoral fellow in the group of Michael Hausmann, Research Group Experimentelle Biophysik at the Kirchhoff-Institute for Physics, Ruprecht-Karls-Universität Heidelberg. topic: 'The GLOBE 3D Genome Information System', in collaboration with T.A. Knoch, Erasmus MC, Rotterdam, The Netherlands.
from 2014 project manager for IT in the groups Genome Organization & Function (Karsten Rippe) and Theoretical Systems Biology (Thomas Höfer) at the german cancer research center (DKFZ) and BioQuant in Heidelberg with focus on data management of deep senqencing and image data, analysis of deep sequencing data, support and teaching, administration of HPC and compute clusters.

Publications

Braun, D.M., Chung, I., Kepper, N. and Rippe, K. (2018). TelNet – a database for human and yeast genes involved in telomere maintenance. BMC Genet 19, 32. doi: 10.1186/s12863-018-0617-8

Kolovos, P., Brouwer, R.W.W., Kockx, C.E.M., Lesnussa, M., Kepper, N., Zuin, J., Imam, A.M.A., van de Werken, H.J.G., Wendt, K.S., Knoch, T.A., van IJcken, W.F.J. and Grosveld, F. (2018). Investigation of the spatial structure and interactions of the genome at sub-kilobase-pair resolution using T2C, Nat Protoc. 13, pp. 459–477. doi: 10.1038/nprot.2017.132.

Deeg, K.I., Chung, I., Poos, A.M., Braun, D.M., Korshunov, A., Oswald, M., Kepper, N., Bender, S., Castel, D., Lichter, P., Grill, J., Pfister, S.M., König, R., Jones, D.T. and Rippe, K. (2017). Dissecting telomere maintenance mechanisms in pediatric glioblastoma. biorxiv 129106. doi: 10.1101/129106.

Knoch, T.A., Wachsmuth, M., Kepper, N., Lesnussa, M., Abuseiris, A., Imam, A.M.A., Kolovos, P., Zuin, J., Kockx, C.E.M., Brouwer, R.W.W., van de Werken, H.J.G., van IJcken, W.F.J., Wendt, K.S. and Grosveld, F.G. (2016). The detailed 3D multi-loop aggregate/rosette chromatin architecture and functional dynamic organization of the human and mouse genomes, Epigenetics Chromatin 9, 58. doi: 10.1186/s13072-016-0089-x.

Teif, V.B., Kepper, N., Yserentant, K., Wedemann, G. and Rippe, K. (2015). Affinity, stoichiometry and cooperativity of heterochromatin protein 1 (HP1) binding to nucleosomal arrays, J. Phys. Condens. Matter 27, 064110. doi: 10.1088/0953-8984/27/6/064110.

Müller, O., Kepper, N., Schöpflin, R., Ettig, R., Rippe, K. and Wedemann, G. (2014). Changing chromatin fiber conformation by nucleosome repositioning, Biophys. J. 107, 2141-2150, doi: 10.1016/j.bpj.2014.09.026.

Kolovos, P., van de Werken, H.J.G., Kepper, N., Zuin, J., Brouwer, R.W.W., Kockx, C.E.M., Wendt, K.S., van IJcken, W.F.J., Grosveld, F., and Knoch, T.A. (2014). Targeted chromatin capture (T2C): a novel high resolution high throughput method to detect genomic interactions and regulatory elements, Epigenetics & Chromatin 7:10, doi:10.1186/1756-8935-7-10.

Grunzke, R., Hesser, J., Starek, J., Kepper, N., Gesing, S., Hardt, M., Hartmann, V., Kindermann, S., Potthoff, J., Hausmann, M., Müller-Pfefferkorn, R., Jäkel, R. (2014). Device-Driven Metadata Management Solutions for Scientific Big Data Use Cases, 2014 22nd Euromicro International Conference on Parallel, Distributed, and Network-Based Processing, pp 317–321, doi: 10.1109/PDP.2014.119.

Zeller, D., Kepper, N., Hausmann, M., and Schmitt, E. (2013). Sequential and Structural Biophysical Aspects of Combinatorial Oligo FISH in Her2/neu Breast Cancer Diagnostics, In International Symposium on Biomedical Engineering and Medical Physics, 10–12 October, 2012, Riga, Latvia IFMBE Proceedings (Dekhtyar, Y., Katashev, A., Lancere, L., eds.) 38, pp. 82–85, Springer, Berlin, Heidelberg, doi: 10.1007/978-3-642-34197-7_21

Schmitt E., Falkner, J., Kepper, N., Weisbecker, A., and Hausmann, M. (2012). A computation service centered business model for clinical diagnostics based on image analysis of microscopic data, International Journal of Economics and Business Modeling 3(3) 192–199.

Dickmann, F., Falkner, J.,Guniac, W., Hampe, J., Hausmann, M., Herrmann, A., Kepper, N., Knoch, T.A., Lauterbach, S., Lippert, J., Peter, K., Schmitt, E., Schwardmann, U., Solodenko, J., Sommerfeld, D., Steinke, T., Weisbecker, A., and Sax, U. (2012). Solutions for biomedical grid computing–Case studies from the D-Grid project Services@MediGRID, Journal of Computational Science 3, 280–297, doi: 10.1016/j.jocs.2011.06.006.

Ettig, R., Kepper, N., Stehr, R., Wedemann, G., and Rippe, K. (2011). Dissecting DNA-histone interactions by molecular dynamics simulations of unwrapping DNA from the nucleosome, Biophys. J. 101, 1999–2008, doi: 10.1016/j.bpj.2011.07.057.

Kepper, N., Ettig, R., Stehr, R., Wedemann, G., and Rippe, K. (2011). Force spectroscopy of chromatin fibers: extracting energetics and structural information from Monte Carlo simulations, Biopolymers 95(7), 435–447.

Löhnhardt, B., Heppner, S., Dickmann, F., Kaspar, M., Quade, M., Skrowny, D., Kepper, N., Krefting, D., Steinke, T., and Sax, U. (2010) Evaluation of Visualization Approaches in a Biomedical Grid Environment. e-Science Workshops, 2010 Sixth IEEE International Conference on, pp. 80–85, doi: 10.1109/eScienceW.2010.22.

Kepper, N., Schmitt, E., Lesnussa, M., Weiland, Y., Eussen, H.B., Grosveld, F.G., Hausmann, M., and Knoch, T.A. (2010) Visualization, analysis, and design of COMBO-FISH probes in the grid-based GLOBE 3D genome platform. Stud. Health Technol. Inform. 159, 171–180.

Kepper, N., Ettig, R., Dickmann, F., Stehr, R., Grosveld, F.G., Wedemann, G., and Knoch, T.A. (2010) Parallel high-performance grid computing: capabilities and opportunities of a novel demanding service and business class allowing highest resource efficiency. Stud. Health Technol. Inform. 159, 264–271.

Stehr, R., Schöpflin, R., Ettig, R., Kepper, N., Rippe, K., and Wedemann, G. (2010) Exploring the conformational space of chromatin fibers and their stability by numerical dynamic phase diagrams. Biophys. J. 98, 1028–1037.

Hübschmann, D., Kepper, N., Cremer, C., and Kreth, G. (2010). Quantitative Approaches to Nuclear Architecture Analysis and Modelling, In Advances in Nuclear Architecture (Adams, N.M. and Freemont, P.S., eds.) pp. 87–129, Springer, Berlin, Heidelberg, ISBN: 978-90-481-9898-6.

Dickmann, F., Kaspar, M., Löhnhardt, B., Kepper, N., Viezens, F., Hertel, F., Lesnussa, M., Mohammed, Y., Thiel, A., Steinke, T., Bernarding, J., Krefting, D., Knoch T.A., and Sax, U. (2009) Visualization in Health Grid Environments: a Novel Service and Business Approach, In Lecture Notes in Computer Science (Altmann, J., Buyya, R. and Rana, O.F., eds.), pp. 150–159. Springer, Berlin, Heidelberg, ISBN: 978-3-642-03863-1, doi: 10.1007/978-3-642-03864-8_12.

Knoch, T. A., Lesnussa, M., Kepper, N., Eussen, H. B., and Grosveld, F. G. (2009). The GLOBE 3D Genome Platform: Towards A Novel System-Biological Paper Tool to Integrate the Huge Complexity of Genome Organization and Function, In Healthgrid Research, Innovation and Business Case (Solomonides, T., Hofmann-Apitius, M., Freudigmann, M., Semler, S. C., Legré, Y. and Kratz, M., eds.), pp. 105–116. IOS Press, Amsterdam, ISBN: 978-1-60750-027-8.

Stehr, R., Kepper, N., Rippe, K., and Wedeman, G. (2008). The effect of the internucleosomal interaction potential on the folding of the chromatin fiber. Biophys. J. 95, 3677–3691.

Rippe, K., Mazurkiewicz, J., and Kepper, N. (2008). Interactions of histones with DNA: nucleosome assembly, stability and dynamics, In DNA interactions with polymers and surfactants (Dias, R. S. and Lindman, B., eds.), pp. 135–172. Wiley, London, ISBN: 978-0-8138-0646-4.

Kepper, N., Foethke, D., Stehr, R., Wedeman, G., and Rippe, K. (2008). Nucleosome geometry and internucleosomal interactions control the chromatin fiber conformation, Biophys. J. 95, 3692–3705.

Shopland, L.S., Lynch, C.R., Peterson, K.A., Thornton, K., Kepper, N., Hase, J., Stein, S., Vincent, S., Molloy, K.R., Kreth, G., Cremer, C., Bult, C.J., and O'Brien, T.P. (2006). Folding and organization of a contiguous chromosome region according to the gene distribution pattern in primary genomic sequence. J. Cell Biol. 174(1), 27–38, doi: 10.1083/jcb.200603083.

Contact

Dr. Nikolaus Kepper

DKFZ & BioQuant Center

Division of Chromatin Networks

Im Neuenheimer Feld 267-BQ24

69120 Heidelberg

Germany

BioQuant room 643

Tel.: +49-6221-54-51441

Fax: +49 6221 54 51487

e-mail: Nick.Kepper (at) bioquant.uni-heidelberg.de

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