Our team develops computer models for the analysis and prediction of biochemical processes in living cells. Particularly, we examine the influence of regulatory RNA molecules which is one of the most important but yet inadequately studied class of molecules. There are three important kinds of long-chained molecules in living cells: DNA (the genetic information), RNA and Proteins.

RNA functions amongst others as the link in the translation of genetic information (DNA) into Proteins, the latter being necessary for all essential processes. RNA molecules play, however, a more important role as previously assumed. Besides their function as a translation template for Proteins, they are also involved in the regulation of cell processes.

We are particularly interested in

• the search for regulatory RNA molecules
• the identification of the mode of action of these RNAs and
• the examination of structural features of RNAs and Proteins

Regulatory RNAs

The regulation of the cell is a complex process whereby a lot of involved elements are not known yet. RNAs influence considerably more processes than previously assumed. Although parts of the genes that are read but not translated into Proteins, the so-called non-coding RNAs, account for 98% of the genetic information, the research focused up to now on parts of the genome that are translated into Proteins which represent only 1% of the DNA.

The determination of the essential parts of the so-called regulatory elements by biochemical procedures is very complex. Since the sequencing of the human genome, however, it is possible to selectively search for those elements with the aid of Bioinformatic approaches. These procedures are assisted by the deciphering of the genetic material of many additional species.

A comparison of the genetic material between related species can now be achieved with the aid of our models. Similarities and differences permit conclusions on regulatory elements. It is not sufficient to search for simple sequence patterns but additional structural properties of the molecules have to be incorporated.

The field of Bioinformatics enables the prediction of RNA structures as their experimental identification is time and resource intensive. The prediction procedures unfortunately have high computational complexity. For this reason, a main part of our work is the optimization of the corresponding procedures.

Regulatory Signals

The determination of regulatory elements provides the first step in uncovering of processes that are being controlled by them. For further analysis, we develop computer models that examine the influence of the regulatory signals in the cell. In this field, we are particularly interested in the effects of the interactions of RNA molecules as well as the cellular selection of the corresponding gene segment.

Main Goals

Regulatory RNAs are engaged in all essential processes of the cell. A faulty RNA regulation can cause serious diseases. Among those are many types of cancer as well as diseases of the nervous system; amongst others Prader-Willi syndrome, autism and Alzheimer's disease. The field of Bioinformatics contributes to the basic understanding of the regulatory mechanisms and permits to establish suitable starting points for treatment.

RNA Structure

Local Sequence-Structure Alignment of RNA (LocARNA) Identification of regulatory RNAs Inverse RNA-Folding Selenoproteins and Protein-Design MARNA: Multiple Alignment of RNA Energy Landscapes

Simplified Protein Models

Protein Structure Prediction Energy Landscapes and Kinetics

Alternative Splicing

Non-EST based prediction of alternative splice events Bioinformatics analysis of alternative splice events at tandem splice sites TassDB: TAndem Splice Site DataBase SNPs affect alternative NAGNAG splicing

Transcriptional Regulation

Modelling and Predicting Transcription Factor Binding Sites Modelling Promoter Logic

Constraint-based Methods for Bioinformatics

Symmetry Breaking Constraint-based Alignment Methods Depth-First Search with dynamic decomposition during search (DDS)

Excellence cluster

BIOSS Excellenzcluster in Freiburg - Biological signalling processes are the key regulators of cellular activity in all types of cells in living organisms. A better understanding of these processes not only provides solutions to important biological problems, but also has a major impact on medical research and practice. The Centre for Biological Signalling Studies (BIOSS) in Freiburg uses modern analytical methods and strategies of synthetic biology to study biological signalling processes in a creative and playful way. The main focus of research at BIOSS is to initiate and promote a dialectic process between scientists using analytical (dissecting) and synthetic (rebuilding) approaches in signalling research.

SFB Project

CRC 992, Project Z01, Deep-Sequencing/Bioinformatics - A molecular understanding of disease mechanisms requires a global approach for studying chromatin states and gene regulation. We will provide our computational infrastructure and expertise in bioinformatics and deep sequencing data analysis to the CRC 992 members to enable the genome-scale study of differential gene expression and DNA methylation patterns in various cell types and organisms. A dedicated data management centre will be developed to facilitate access, visualisation and routine analysis of the sequencing data. We will also offer regular training with a special focus on the web services provided by our group. We will thereby help to improve the capacity for epigenetic research towards the development of potential epigenetic therapies.

Ideenwettbewerb Biotechnologie und Medizintechnik

A synthetic switch mechanism to control the function and localization of protein in animal and human cells The topic of this endeavour is the development and characterization of a novel synthetic biological switch mechanism, allowing to gain time-resolved control over the function and the localization of a selected protein in animal and human cells. In order to realize the idea, a novel class of synthetic biological switches was to be developed, which allow, dependend on the presence of a low molecular signal molecule, a fusion of a user-defined target protein onto a second protein, such that the second protein is able to control the functionality, activity or even the localization of the first protein. The results of the funded "Ideenwettbewerb Biotechnologie und Medizintechnik" feasibility study were presented from 16th to 18th of January 2012 in the house of economy in Stuttgart. Out of 42 displayed projects 10 were recommended for further funding. About 150 protagonists of the fields of politics, research, science and economy participated at the event of the Ministry of Science, Research and Economy of the state Baden-Württemberg, which was additionally supported by "Projektträger Jülich" and the BIOPRO Baden-Württemberg initiative. Within the category "Synthetic Biology", Prof. Dr. R. Backofen's and Prof. Dr. W. Weber's project "A synthetic switch mechanism to control the function and the localization of protein in animal and human cells" was nominated worthy to receive further funding.

DFG Projects

DFG Project: Bioinformatic analyses of CRISPR elements - Forschergruppe (FOR 1680) Unravelling the prokaryotic immune system Prokaryotes acquire immunity against phages and viruses through a gene silencing pathway mediated by clusters of regularly interspaced short palindromic repeats, so-called CRISPR non-coding RNAs. This proposal aims to elucidate the mechanism underlying the processing of CRISPR-transcripts, targeting specificity of mature crRNA, and acquisition of new spacers using advanced bioinformatics tools. A complex of CRISPR-associated (Cas) proteins is known to process the CRISPR-transcripts and binds to a sequence/structure motif within the direct repeats. We use two approaches to predict the important secondary structure elements: We will analyse families of all known CRISPR repeats. We will investigate the influence of the context sequence (flanking spacers) on the repeat structure and calculate structure quality measures for each occurrence. Mature crRNA targets either single-stranded RNA or double-stranded DNA. We will scan metagenomic data for novel proto-spacers, which are invading DNA/RNA that match a CRISPR-spacer and represent a putative target. With this set of proto-spacers, we will determine characteristic features of targeting single-stranded RNA, e.g. the interaction hybridization strength, accessibility of the target site, and various kinetic features. Based on experimental data for RNA-DNA interaction, we will also develop a novel classification approach for RNA-DNA interaction. Current data indicates an R-loop interaction, and we will combine sequence-based features of DNA-duplex stability with features from the predicted R-loop interaction.
DFG Projekt: Extending the theory of Algebraic Dynamic Programming for applications in bioinformatics Dynamic programming techniques are the basis of many algorithms used in bioinformatics, as for example the alignment methods used in comparative genomics or algorithms for RNA structure prediction. New insights lead to a continuous improvement of those algorithms and the development of many specialized variants. As a consequence, there is a growing demand to implement efficient prototypes of these algorithms quickly. This is in particular hard since for specialized problems the recursive structure of the corresponding dynamic programming algorithm becomes more and more complex. Algebraic Dynamic Programming (ADP) has been proven to be a suitable framework for the rapid development and efficient implementation of dynamic programming algorithms in bioinformatics. In this work we want to extend the theory of ADP to make it applicable to a larger class of problems, make it more efficient, and more convenient to use. In particular, we want to formulate the problems of RNA pseudoknot alignment and RNA-RNA-interaction in ADP. Furthermore, we investigate how various optimization techniques that have been applied to dynamic programming algorithms recently, can be integrated in the ADP framework. This does not only lead to more efficient implementations, but also to a more precise and fundamental understanding of the optimizations and the circumstances under which they can be applied. Finally, we want to extend ADP with better support for probabilistic models which is essential for many applications.
DFG Priority Program SPP 1395 : Informations- und Kommunikationstheorie in der Molekularbiologie (InKoMBio) MicroRNA as an integral part of cell communication: Regularized target prediction and network prediction MicroRNAs, gene encoded small RNA molecules, play an integral part in gene regulation by binding to target mRNAs and preventing their translation. The prediction of microRNA-mRNA binding sites and the resulting interaction network are essential to understand, and thus influence, regulation of a genetic information flow inside the living organism. Numerous algorithms have been proposed based on various heuristics; however the predictions often vary considerably. In this project we will extend a physical model for the binding of microRNAs to the corresponding target and establish an extended set of features influencing binding probabilities. We will be faced with the challenge of (i) too many features and (ii) few known interactions on which to train any prediction algorithm. This problem will be solved by using (i) information-theoretical criteria for feature reduction, (ii) regularization, (iii) application of the Infomax approach to guarantee minimal loss of information after dimension reduction, and (iv) experimental validation of theoretical predictions using a novel test system. This strategy will allow (i) statistical analysis of the predicted microRNA-mRNA hypergraph, (ii) characterization of network motives and hierachies, (iii) identification of missing links and (iv) removal of false interactions. The project is in collaboration with Prof. Dr. Klaus Palme - Albert-Ludwigs-Universität Freiburg, Institut für Biologie II / Botanik Prof. Dr. Fabian Theis - Helmholtz Zentrum München, Institut für Bioinformatik und Systembiologie
DFG Project : A Flexible and Efficient System for the Detection of RNA Sequence/Structure Motifs In this project, we concentrate on algorithmic approaches for the comparison of RNAs. The comparison of RNAs requires to consider both the sequence and structure of the RNAs. We want to overcome the limitations of existing approaches in both expressivity and efficiency. We will investigate three directions: We will study different means for improving the quality of RNA alignment algorithms. Thus, we will study different types of local RNA alignment algorithms (both sequence locality and a more recent new notion called structure locality), since RNA motifs are of local nature. Furthermore, we will consider an important class of structures (pseudoknots) usually not handled by RNA alignment tools. Current RNA alignment algorithms are too time costly. We propose to study how different optimization techniques successfully applied to sequence alignment can be used in RNA alignment. We will also perform tasks required for the success in practical applications. Thus, we plan to develop new filtering techniques for fast search of RNA motifs in genome databases, which is a necessary prerequisite to promote research on functional RNAs. We will investigate approaches for improving progressive multiple RNA alignment, and will train parameters on benchmark sets. This will also allow us to investigate the properties of the introduced scoring systems. Since any development will be incorporated into our widely used multiple alignment system LocARNA, this will produce one of the most advanced system for defining and searching various types of RNA motifs. The project is in collaboration with Prof. Gad M. Landau, University of Haifa, Israel.
DFG Priority Program SPP 1258 : Sensory and regulatory RNAs in Prokaryotes Detection of novel ncRNAs in prokaryotes and investigation of structural/functional features within them, as well as analysis of the interaction between bacterial ncRNAs and their target mRNAs.

Completed Projects

DFG SFB 604 - Project B10: Alternative splicing as a modulator of signal transduction
EU project EMBIO: Emergent Organisation in Complex Biomolecular Systems
EU Network of Excellence REWERSE: Reasoning on the Web with Rules and Semantics - Working Group A2 - Adding Semantics to the Bioinformatics Web
DFG Priority Program 'Selenoproteins' : Using Bioinformatics Methods to Search for Unknown Alternative Splice Forms of Selenoproteins. (BA 2168/1-2)

BMBF Projects

BMBF/JCB Project D.5: Regulatory Elements BMBF Project D.6 BMBF-project Freiburg Initiative for Systems Biology (FRISYS) - WP 2 and WP 3 The programmatic focus of FRISYS is modelling and system analysis of signalling processes in growth and differentiation of well developed model organisms at phylogenetic key positions.