BIOQUANT

Open Positions

Master/Diploma students

The group Genome Organization & Function at the BioQuant conducts several interdisciplinary research projects with funding from different sources. Our current research activities are described on the Publications and Research pages. We are looking Bachelor/Master students (please contact us for projects) as well as PhD students and Post-docs with background/interest in either Molecular/Cell Biology, Physics or Computer Science (see below for open positions).

PhD and Postdocs

Open positions in various research initatives (see our funding sources) are listed below under "Positions available". Alternatively, you may apply for PhD and Postdoc fellowships in various programs. As a group of the Deutsches Krebsforschungszentrum (DKFZ) we participate in the DKFZ International PhD Program, which offers 36 fellowships each year. Our group is part of the "Research Program B: Functional and Structural Genome Research". In addition, our group is a member of the Cluster of Excellence CellNetworks in Heidelberg and the HBIGS Graduate School of Molecular and Cellular Biology. Please feel free to contact us for further information on the the various PhD programs or other fellowship applications or positions available from third-party funding (DFG, BMBF etc.) of our research projects.

PhD fellowships

Post-doc fellowships

Short term visits (3-6 months)

Postdoc/PhD positions are currently available for the following research topics:

(contact: Karsten Rippe)

Understanding deregulated epigenetic gene silencing networks in cancer (Postdoc/PhD student)

Start: Summer 2014

Project: Epigenetics is being recognized as pivotal to numerous fields of medical research including cancer, developmental diseases and the reprogramming of adult somatic cells into stem cells. The associated mechanisms are already being exploited for disease diagnosis and treatments by new generation of anti-cancer drugs. However, such drugs affect epigenetic modifications in the genome in complex and poorly understood ways. Thus, there is an urgent need for predictive models of epigenetic regulatory networks.

Epigenetic regulation operates via DNA methylation, covalent modifications of histone tails, nuclear RNAs and protein-protein/DNA interactions of histones and other chromosomal proteins. These factors control the DNA accessibility and thus gene transcription, DNA replication, repair and recombination. It is now becoming clear that the various epigenetic players interact in a complex and highly dynamic network to induce, propagate or reverse functional states of chromatin.

Within our group large scale data sets for mouse embryonic stem cells as well as B-lymphocytes from patients with chronic lymphocytic leukemia are available. The ongoing projects involve the analysis of genome-wide sequencing data that reflect both (epi)genomic states and spatial chromatin organization to model how epigenetic signals are read out and are linked to nucleosome positioning, chromatin fiber folding and the binding of transcription factors.

The work will be conducted in a team that conducts experimental studies as well as bioinformatical analysis and numerical computer simulations to develop models on how functional chromatin states are established. Thus, the work could reside on either the experimental or on the theoretical side. The aim is it to integrate DNA sequence information, epigenetic modifications, chromatin structure and dynamics at different scales to explain how gene expression becomes deregulated in cancer. Results and predictions from the modeling work are tested and further refined against experimental data. The work is being conducted within a consortium of several groups (see www.CancerEpiSys.org) in the BMBF CancerSys program.

Previous training: Candidates should have a masters/PhD degree with a focus on Molecular Biology/Biotechnology, Biophysics, Systems Biology, Physics or Computer Sciences. Interest in interdisciplinary work is expected as well as knowledge/interest in one or more of the following areas: mechanistic analysis of gene expression regulation, genome-wide mapping of chromatin features and RNA by DNA sequencing data (ChIP-seq, RNA-seq etc.).

References

Erdel, F., Müller-Ott, K. & Rippe, K. (2013). Establishing epigenetic domains via chromatin-bound histone modifiers. Ann. N. Y. Acad. Sci. 1305, 29-43. doi: 10.1111/nyas.12262 | Abstract | Reprint (0.8 MB).

Toiber, D., Erdel, F., Silberman, D. M., Zhong, L., Mulligan, P., Bouazoune, K., Sebastian, C., Cosentino, C., Martinez-Pastor, B., Giacosa, S., D'Urso, A., Naar, A., Kingston, R., Rippe, K. & Mostoslavsky, R. (2013). SIRT6 recruits SNF2H to sites of DNA breaks, preventing genomic instability through chromatin remodeling. Mol. Cell 51, 454-468. doi: 10.1016/j.molcel.2013.06.018 | Abstract | Reprint (6.2 MB).

Jäger, N., Schlesner, M., Jones, D. T. W., Raffel, S., Mallm, J.-P., Junge, K. M., Weichenhan, D., Bauer, T., Ishaque, N., Kool, M., Northcott, P. A., Korshunov, A., Drews, R. M., Koster, J., Versteeg, R., Richter, J., Hummel, M., Mack, S. C., Taylor, M. D., Witt, H., Swartman, B., Schulte-Bockholt, D., Sultan, M., Yaspo, M.-L., Lehrach, H., Hutter, B., Brors, B., Wolf, S., Plass, C., Siebert, R., Trumpp, A., Rippe, K., Lehmann, I., Lichter, P., Pfister, S. M., Eils, R. (2013). Hypermutation of the inactive X chromosome is a frequent event in cancer. Cell 155, 567-581. doi: 10.1016/j.cell.2013.09.042 | Abstract | Reprint (2.9 MB).

Teif, V. B., Vainshtein, Y., Caudron-Herger, M., Mallm, J.-P., Marth, C., Höfer, T. & Rippe, K. (2012). Genome-wide nucleosome positioning during embryonic stem cell development. Nat. Struct. Mol. Biol. 19, 1185-1191. doi: 10.1038/nsmb.2419 | Abstract | Reprint (7.4 MB)

Mapping protein mobility and interactions in living cells by spatiotemporal fluctuation microscopy (Postdoc/PhD student)

Start: Summer 2014

Project: The cell nucleus is a highly dynamic place: proteins diffuse through the nucleoplasm, associate into complexes or interact with parts of the genome to regulate gene expression or mediate DNA repair. To investigate these processes, the combination of fluorescence bleaching and correlation methods in conjunction with an integrative multi-scale analysis of the corresponding data sets is ideally suited. It allows the determination of parameters like intracellular concentration, association state, diffusion coefficient, kinetic binding and dissociation rate constants. From spatially resolved measurements, protein mobility maps can be constructed that reveal local changes in genome accessibility and interactions for the proteins studied. To implement this approach a parallel data acquisition setup is highly advantageous. This is accomplished with a novel fluorescence microscope system. It is designed for fast confocal imaging and simultaneous fluorescence correlation spectroscopy measurements at hundreds of spots along a line. By advancing data acquisition and analysis this setup is applied to studies of protein interactions with respect to the following questions: (i) How are specific patterns of epigenetic histone and DNA modifications established? (ii) How is genome access affected by chromatin signals, for example by histone acetylation? (iii) How to chemotherapeutic drugs like doxorubicin or histone deacteylase inhibitors change genome access and protein transport?

Previous training: Candidates should have a master/PhD in Physics, Chemistry or Biology and interest in the advancement of fluorescence microscopy/spectroscopy techniques and associated data analysis.

References

Baum, M., Wachsmuth, M., Erdel, F. & Rippe, K. (2014). Mapping the intracellular structure from a diffusing protein's point of view, under revision.

Erdel, F. & Rippe, K. (2012). Quantifying transient binding of ISWI chromatin remodelers in living cells by pixel-wise photobleaching profile evolution analysis. Proc. Natl. Acad. Sci. USA 109, E3221-E3230. doi: 10.1073/pnas.1209579109 | Abstract | Reprint (3.4 MB)

Erdel, F., Schubert, T., Marth, C., Längst, G. & Rippe, K. (2010). Human ISWI chromatin-remodeling complexes sample nucleosomes via transient binding reactions and become immobilized at active sites. Proc. Natl. Acad. Sci. USA 107, 19873-19878. Abstract | Reprint (1.4 MB) | Commtent 1 | Comment 2

Erdel, F., Müller-Ott, K. P., Baum, M., Wachsmuth, M. & Rippe, K. (2010). Dissecting chromatin interactions in living cells from protein mobility maps. Chromosome Res. 19, advance online publicatione 17 September 2010. Abstract | Reprint (0.6 MB)

Heuvelmann, G., Erdel, F., Wachsmuth, M. & Rippe, K. (2009). Analysis of protein mobilities and interactions in living cells by multi-focal fluorescence fluctuation microscopy. Eur. Biophys. J. 38, 813-828. Abstract | Reprint (0.8 MB pdf file)

Müller, K. P., Erdel, F., Caudron, M., Marth, C., Fodor, B. D., Richter, M., Scaranaro, M., Beoudoin, J., Wachsmuth, M. & Rippe, K. (2009). A multi-scale analysis of dynamics and interactions of heterochromatin protein 1 in the nucleus by fluorescence fluctuation microscopy, Biophys. J. 97, 2876-2885. Abstract | Reprint (3.3 MB pdf file)

Identifying cancer telomere maintenance networks for diagnosis, prognosis, patient stratification and therapy response prediction (Postdoc/PhD student)

Start: Summer 2014

Project: Cancer cells require a telomere maintenance mechanism (TMM) to avoid cellular senescence and apoptosis induced by the replicative shortening of their chromosome ends. Frequently, telomerase is reactivated to extend the telomeres. However, in 5-25 % of the cases (depending on tumor entity) alternative lengthening of telomeres (ALT) pathways exist that operate via DNA repair and recombination processes.

The identification of the active TMM provides highly valuable information from which prognostic and stratifying analysis schemes can be derived that address the clinically observed tumor heterogeneity. For example, the presence of a specific TMM in glioblastoma and lymphoma is a prognostic marker for patient survival. Since cancer therapies targeting telomerase can select for the emergence of an ALT-positive cancer cell population, specific assays and treatments for the different TMM subgroups are needed to diagnose and target these recurrent tumors.

Within a consortium project that involves several groups at the DKFZ and the University of Heidelberg, we are implementing a systems medicine approach that integrates a bioinformatical analysis of (epi)genomic data with automated high-throughput quantification of 3D fluorescence microscopy images to develop network models that describe the active TMM of a given tumor patient sample. In an iterative cycle between experimental studies and modeling work, we will derive a TMM classification scheme for the TMM status in glioblastoma and prostate cancer samples for which we have already identified the presence of clinically relevant subgroups with different TMMs.

The TMM classification will be applied in a clinical setting for prognostic, predictive and stratifying analysis of tumor samples. Furthermore, we will develop strategies to combine existing telomerase inhibitors with novel approaches that target ALT and promote telomere repeat resection for improving the application of TMM inhibition in cancer therapy and will identify specific drug targets for the different TMM subgroups based on the network models. The work is being conducted within a consortium of several groups (see www.CancerTelSys.org) in the BMBF e:Med program.

Previous training: Candidates should have a background in Cell/Molecular Biology, Biophysics or Bioinformatics. In the project two positions are available with one having the focus on the experimental work and the other on the analysis of genome-wide sequencing data and/or imaging data to derive mechanistic network models for telomere maintenance. Interest in interdisciplinary work is expected as well as knowledge/interest in one or more of the following areas: Chromosome and cell nucleus organization, telomeres, RNAi screening, fluorescence microscopy, genome-wide sequencing methods.

References

Chung, I., Osterwald, S., Deeg, K. & Rippe, K. (2012). PML body meets telomere: The beginning of an ALTernate ending. Nucleus 3, 263-275. doi: 10.4161/nucl.20326 | Abstract | Reprint (2.3 MB)

Osterwald, S., Wörz, S., Reymann, J., Sieckmann, F., Rohr, K., Erfle, H. & Rippe, K. (2012). A three-dimensional colocalization RNA interference screening platform to elucidate the alternative lengthening of telomeres pathway. Biotechnol. J. 7, 103-116. doi: 10.1002/biot.201000474 | Abstract | Reprint (1.8 MB)

Chung, I., Leonhardt, H. & Rippe, K. (2011). De novo assembly of a PML nuclear subcompartment occurs through multiple pathways and induces telomere elongation. J. Cell Sci. 124, 3603-3618. doi: 10.1242/jcs.084681 | Abstract | Reprint (9.4 MB) | Comment

Lang, M., Jegou, T., Chung, I., Richter, K., Udvarhelyi, A., Münch, S., Cremer, C., Hemmerich, P., Engelhardt, J., Hell, S. W. & Rippe, K. (2010). Three-dimensional organization of PML nuclear bodies. J. Cell Sci. 123, 392-400. Abstract | Reprint (4.3 MB pdf file) | Comment

Jegou, T., Chung, I., Heuvelmann, G., Wachsmuth, M., Görisch, S. M., Greulich-Bode, K., Boukamp, P., Lichter, P. & Rippe, K. (2009). Dynamics of telomeres and promyelocytic leukemia nuclear bodies in a telomerase negative human cell line. Mol Biol Cell 20, 2070-2082. Abstract | Reprint (3.3 MB pdf file).

 

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