European Molecular Biology Laboratory Heidelberg

Heidelberg, Germany

European Molecular Biology Laboratory Heidelberg

Heidelberg, Germany

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Hocevar Brezavscek A.,Jozef Stefan Institute | Hocevar Brezavscek A.,University of Pennsylvania | Rauzi M.,European Molecular Biology Laboratory Heidelberg | Leptin M.,European Molecular Biology Laboratory Heidelberg | And 2 more authors.
Biophysical Journal | Year: 2012

We propose a 2D mechanical model of a tubular epithelium resembling the early Drosophila embryo. The model consists of a single layer of identical cells with energy associated with the tension of cell cortex. Depending on the relative tension of the apical, basal, and lateral sides of the cells, tissue thickness, and the degree of external constraint, the minimal-energy states of the epithelial cross section include circular shapes as well as a range of inward-buckled shapes. Some of the solutions are characterized by a single deep groove, which shows that an epithelium consisting of cells of identical mechanical properties can infold. This is consistent with what is seen in embryos of certain Drosophila mutants. To ensure that the infolding occurs at a predetermined section of the epithelium, we extend the model by increasing the cross-sectional area of a subset of cells, which is consistent with observations in wild-type embryos. This variation of cell parameters across the epithelium is sufficient to make it fold at a specific site. The model explores previously untested minimal conditions for tissue invagination and is devoid of specificity needed to accurately describe an in vivo situation in Drosophila. © 2012 Biophysical Society.


Wang Y.,Max Planck Institute of Psychiatry | Wang Y.,European Molecular Biology Laboratory Heidelberg | Kirschner A.,Max Planck Institute of Psychiatry | Fabian A.-K.,Max Planck Institute of Psychiatry | And 9 more authors.
Journal of Medicinal Chemistry | Year: 2013

The design of efficient ligands remains a key challenge in drug discovery. In the quest for lead-like ligands for the FK506-binding protein 51 (FKBP51), we designed two new classes of bicyclic sulfonamides to probe the contribution of conformational energy in these ligands. The [4.3.1] scaffold had consistently higher affinity compared to the [3.3.1] or monocyclic scaffolds, which could be attributed to better preorganization of two key recognition motifs. Surprisingly, the binding of the rigid [4.3.1] scaffold was enthalpy-driven and entropically disfavored compared to the flexible analogues. Cocrystal structures at atomic resolution revealed that the sulfonamide nitrogen in the bicyclic scaffolds can accept an unusual hydrogen bond from Tyr113 that mimics the putative FKBP transition state. This resulted in the first lead-like, functionally active ligand for FKBP51. Our work exemplifies how atom-efficient ligands can be achieved by careful conformational control even in very open and thus difficult binding sites such as FKBP51. © 2013 American Chemical Society.


Rauzi M.,European Molecular Biology Laboratory Heidelberg | Hocevar Brezavscek A.,Rockefeller University | Hocevar Brezavscek A.,Jozef Stefan Institute | Ziherl P.,Jozef Stefan Institute | And 2 more authors.
Biophysical Journal | Year: 2013

The invagination of the mesoderm in the Drosophila melanogaster embryo is an intensely studied example of epithelial folding. Several theoretical studies have explored the conditions and mechanisms needed to reproduce the formation of the invagination in silico. Here we discuss the aspects of epithelial folding captured by these studies, and compare the questions addressed, the approaches used, and the answers provided. © 2013 Biophysical Society.


Durdu S.,European Molecular Biology Laboratory Heidelberg | Iskar M.,European Molecular Biology Laboratory Heidelberg | Revenu C.,European Molecular Biology Laboratory Heidelberg | Revenu C.,University Pierre and Marie Curie | And 5 more authors.
Nature | Year: 2014

Morphogenesis is the process whereby cell collectives are shaped into differentiated tissues and organs. The self-organizing nature of morphogenesis has been recently demonstrated by studies showing that stem cells in three-dimensional culture can generate complex organoids, such as mini-guts, optic-cups and even mini-brains. To achieve this, cell collectives must regulate the activity of secreted signalling molecules that control cell differentiation, presumably through the self-assembly of microenvironments or niches. However, mechanisms that allow changes in tissue architecture to feedback directly on the activity of extracellular signals have not been described. Here we investigate how the process of tissue assembly controls signalling activity during organogenesis in vivo, using the migrating zebrafish lateral line primordium. We show that fibroblast growth factor (FGF) activity within the tissue controls the frequency at which it deposits rosette-like mechanosensory organs. Live imaging reveals that FGF becomes specifically concentrated in microluminal structures that assemble at the centre of these organs and spatially constrain its signalling activity. Genetic inhibition of microlumen assembly and laser micropuncture experiments demonstrate that microlumina increase signalling responses in participating cells, thus allowing FGF to coordinate the migratory behaviour of cell groups at the tissue rear. As the formation of a central lumen is a self-organizing property of many cell types, such as epithelia and embryonic stem cells, luminal signalling provides a potentially general mechanism to locally restrict, coordinate and enhance cell communication within tissues. ©2014 Macmillan Publishers Limited. All rights reserved.


Redemann S.,Max Planck Institute of Molecular Cell Biology and Genetics | Schloissnig S.,European Molecular Biology Laboratory Heidelberg | Ernst S.,Max Planck Institute of Molecular Cell Biology and Genetics | Pozniakowsky A.,Max Planck Institute of Molecular Cell Biology and Genetics | And 3 more authors.
Nature Methods | Year: 2011

We present a method to control protein levels under native genetic regulation in Caenorhabditis elegans by using synthetic genes with adapted codons. We found that the force acting on the spindle in C. elegans embryos was related to the amount of the G-protein regulator GPR-1/2. Codon-adapted versions of any C. elegans gene can be designed using our web tool, C. elegans codon adapter. © 2011 Nature America, Inc. All rights reserved.


Conrad C.,European Molecular Biology Laboratory Heidelberg | Gerlich D.W.,ETH Zurich
Journal of Cell Biology | Year: 2010

Fluorescence microscopy is one of the most powerful tools to investigate complex cellular processes such as cell division, cell motility, or intracellular trafficking. The availability of RNA interference (RNAi) technology and automated microscopy has opened the possibility to perform cellular imaging in functional genomics and other large-scale applications. Although imaging often dramatically increases the content of a screening assay, it poses new challenges to achieve accurate quantitative annotation and therefore needs to be carefully adjusted to the specific needs of individual screening applications. In this review, we discuss principles of assay design, large-scale RNAi, microscope automation, and computational data analysis. We highlight strategies for imaging-based RNAi screening adapted to different library and assay designs. © 2010 Conrad and Gerlich.


Thoma C.R.,ETH Zurich | Thoma C.R.,Brigham and Women's Hospital | Thoma C.R.,Harvard University | Matov A.,Scripps Research Institute | And 7 more authors.
Journal of Cell Biology | Year: 2010

Von Hippel-Lindau (VHL) tumor suppressor gene mutations predispose carriers to kidney cancer. The protein pVHL has been shown to interact with microtubules (MTs), which is critical to cilia maintenance and mitotic spindle orientation. However, the function for pVHL in the regulation of MT dynamics is unknown. We tracked MT growth via the plus end marker EB3 (end-binding protein 3)-GFP and inferred additional parameters of MT dynamics indirectly by spatiotemporal grouping of growth tracks from live cell imaging. Our data establish pVHL as a near-optimal MT-stabilizing protein: it attenuates tubulin turnover, both during MT growth and shrinkage, inhibits catastrophe, and enhances rescue frequencies. These functions are mediated, in part, by inhibition of tubulin guanosine triphosphatase activity in vitro and at MT plus ends and along the MT lattice in vivo. Mutants connected to the VHL cancer syndrome are differentially compromised in these activities. Thus, single cell-level analysis of pVHL MT regulatory function allows new predictions for genotype to phenotype associations that deviate from the coarser clinically defined mutant classifications. © 2010 Thoma et al.


Joosten R.P.,Netherlands Cancer Institute | Te Beek T.A.H.,Radboud University Nijmegen | Krieger E.,Radboud University Nijmegen | Hekkelman M.L.,Radboud University Nijmegen | And 4 more authors.
Nucleic Acids Research | Year: 2011

The Protein Data Bank (PDB) is the world-wide repository of macromolecular structure information. We present a series of databases that run parallel to the PDB. Each database holds one entry, if possible, for each PDB entry. DSSP holds the secondary structure of the proteins. PDBREPORT holds reports on the structure quality and lists errors. HSSP holds a multiple sequence alignment for all proteins. The PDBFINDER holds easy to parse summaries of the PDB file content, augmented with essentials from the other systems. PDB-REDO holds re-refined, and often improved, copies of all structures solved by X-ray. WHY NOT summarizes why certain files could not be produced. All these systems are updated weekly. The data sets can be used for the analysis of properties of protein structures in areas ranging from structural genomics, to cancer biology and protein design. © The Author(s) 2010.


Bassel G.W.,European Molecular Biology Laboratory Heidelberg | Bassel G.W.,University of Nottingham | Glaab E.,University of Nottingham | Marquez J.,European Molecular Biology Laboratory Heidelberg | And 4 more authors.
Plant Cell | Year: 2011

The author responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (www.plantcell.org) is: George W. Bassel (george.bassel@nottingham.ac.uk). The meta-analysis of large-scale postgenomics data sets within public databases promises to provide important novel biological knowledge. Statistical approaches including correlation analyses in coexpression studies of gene expression have emerged as tools to elucidate gene function using these data sets. Here, we present a powerful and novel alternative methodology to computationally identify functional relationships between genes from microarray data sets using rulebased machine learning. This approach, termed "coprediction," is based on the collective ability of groups of genes cooccurring within rules to accurately predict the developmental outcome of a biological system. We demonstrate the utility of coprediction as a powerful analytical tool using publicly available microarray data generated exclusively from Arabidopsis thaliana seeds to compute a functional gene interaction network, termed Seed Co-Prediction Network (SCoPNet). SCoPNet predicts functional associations between genes acting in the same developmental and signal transduction pathways irrespective of the similarity in their respective gene expression patterns. Using SCoPNet, we identified four novel regulators of seed germination (ALTERED SEED GERMINATION5, 6, 7, and 8), and predicted interactions at the level of transcript abundance between these novel and previously described factors influencing Arabidopsis seed germination. An online Web tool to query SCoPNet has been developed as a community resource to dissect seed biology and is available at http://www.vseed.nottingham.ac.uk/.© 2011 American Society of Plant Biologists.


Grubert F.,Stanford University | Zaugg J.B.,Stanford University | Zaugg J.B.,European Molecular Biology Laboratory Heidelberg | Kasowski M.,Stanford University | And 17 more authors.
Cell | Year: 2015

Summary Deciphering the impact of genetic variants on gene regulation is fundamental to understanding human disease. Although gene regulation often involves long-range interactions, it is unknown to what extent non-coding genetic variants influence distal molecular phenotypes. Here, we integrate chromatin profiling for three histone marks in lymphoblastoid cell lines (LCLs) from 75 sequenced individuals with LCL-specific Hi-C and ChIA-PET-based chromatin contact maps to uncover one of the largest collections of local and distal histone quantitative trait loci (hQTLs). Distal QTLs are enriched within topologically associated domains and exhibit largely concordant variation of chromatin state coordinated by proximal and distal non-coding genetic variants. Histone QTLs are enriched for common variants associated with autoimmune diseases and enable identification of putative target genes of disease-associated variants from genome-wide association studies. These analyses provide insights into how genetic variation can affect human disease phenotypes by coordinated changes in chromatin at interacting regulatory elements. © 2015 Elsevier Inc.

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