The transcription rate of a gene is regulated by the coordinated binding of activating or repressing transcription factors at its promoter and cis-regulatory elements. To be able to understand the molecular computation which transforms factor concentrations into a transcriptional output, we need to know the precise binding affinities of the factors involved. Nutiu et al. (Nature Biotechnology 2011) have demonstrated a high-throughput method (high-throughput sequencing - fluorescent ligand interaction profiling, or HiTS-FLIP) with which one can measure the binding constants of a protein factor to tens of millions of DNA sequences at a time in a single lane of a high-throughput sequencer. Using this method, charting the binding landscapes of thousands of factors in humans and model organisms seems within reach. This should allow the accurate prediction of regulatory network topologies, factor binding strengths and transcription rates.

 

In the framework of the BioSysNet network, we will develop theoretical methods and software to analyze and interpret these measurements and to derive models parameterizing the binding landscapes that allow for the dependence between motif positions. We further plan to use HiTS-FLIP to analyze the cooperative binding energy landscapes of interacting pairs of factors. Our work will contribute to a quantitative modeling of transcriptional regulation and to enabling a system-level description of regulatory networks in development and disease.

 

Vincent Wolowski

 

Seemayer S, Gruber M, Söding J (2014). CCMpred-fast and precise prediction of protein residue-residue contacts from correlated mutations. Bioinformatics. [Epub ahead of print]

 

Runge S, Sparrer KM, Lässig C, Hembach K, Baum A, García-Sastre A, Söding J, Conzelmann KK, Hopfner KP (2014). In vivo ligands of MDA5 and RIG-I in measles virus-infected cells. PLoS Pathog 10(4):e1004081.

 

Meinel DM, Burkert-Kautzsch C, Kieser A, O'Duibhir E, Siebert M, Mayer A, Cramer P, Söding J, Holstege FC, Sträßer K (2013). Recruitment of TREX to the transcription machinery by its direct binding to the phospho-CTD of RNA polymerase II. PLoS Genet 9(11):e1003914. 

• Close P., East P., Dirac-Svejstrup A. B., Hartmann H., Heron M., Maslen S., Chariot A., Söding J., Skehel M., and Svejstrup J. Q. DBIRD integrates alternative mRNA splicing with RNA polymerase II transcript elongation. Nature, in press (2012) doi:10.1038/nature10925.

 

• Remmert M., Biegert A., Hauser A., and Söding J. HHblits: Lightning-fast iterative protein sequence searching by HMM-HMM alignment. Nat Methods, 9:173-175 (2011).

 

• Seizl M., Hartmann H., Hoeg F., Kurth F., Martin D. E., Söding J., and Cramer P. A functional GA element in TATA-less RNA polymerase II promoters. PLoS ONE 6: e27595 (2011).

 

• Feller C., Prestel M., Hartmann H., Straub T., Söding J., and Becker P.

The MOF-containing NSL complex associates globally with housekeeping genes, but activates only a defined subset. Nucleic Acids Res. 40:1509-1522 (2011).

 

• Higgins D., Sievers F., Wilm A., Dineen D., Gibson T., Karplus K., Li W., Lopez R., McWilliam H., Remmert M., Söding J., Thompson J. Fast, scalable generation of high quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 7:539 (2011).

 

• Söding J. and Remmert M. Protein sequence comparison and fold recognition: progress and good-practice benchmarking. Curr Opin Struct Biol 21:404-411 (2011).

 

• Lammens K., Bemeleit D. J., Möckel C., Clausing E., Schele A., Hartung S., Schiller C. B., Lucas M., Angermüller C., Söding J., Sträßer, and Hopfner K.-P. X-ray structure of a bacterial Mre11:Rad50 complex reveals an ATP dependent molecular clamp in DNA double-strand break repair. Cell 145:54-66 (2011).

 

• Frauer C., Rottach A., Meilinger D., Bultmann S., Fellinger K., Hasenoeder S., Söding J., Spada F., Leonhardt H. Different binding properties and function of CXXC zinc finger domains in Dnmt1 and Tet1. PLoS ONE 6: e16627 (2011).

 

• Armache J. P., Jarasch A., Anger A. M., Villa E., Becker T., Bhushan S., Jossinet F., Habeck M., Dindar G., Franckenberg S., Marquez V., Mielke T., Thomm M., Berninghausen O., Beatrix B., Söding J., Westhof E., Wilson D. N., Beckmann R. Localization of eukaryote-specific ribosomal proteins in a 5.5Å cryo-EM map of the 80S eukaryotic ribosome. Proc Natl Acad Sci USA. 107:19754-19759 (2010).

 

• Armache J. P., Jarasch A., Anger A. M., Villa E., Becker T., Bhushan S., Jossinet F., Habeck M., Dindar G., Franckenberg S., Marquez V., Mielke T., Thomm M., Berninghausen O., Beatrix B., Söding J., Westhof E., Wilson D. N., Beckmann R. Cryo-EM structure and rRNA model of a translating eukaryotic 80S ribosome at 5.5-A resolution. Proc Natl Acad Sci USA. 107:19748-19753 (2010).

 

• Graebsch A., Roche S., Kostrewa D., Söding J., and Niessing D. Of Bits and Bugs - on the Use of Bioinformatics and a Bacterial Crystal Structure to Solve a Eukaryotic Repeat-protein Structure. PLoS ONE 5:e13402 (2010).

 

• Mayer A*., Lidschreiber M*., Siebert M*., Leike K., Söding J., and Cramer P.

Uniform transitions of the general RNA polymerase II transcription complex. Nat Struct Mol Biol. 17:1272-1278 (2010). (*) Shared first authors.

 

• Böttger A., Lasi M., Pauly B., Schmidt N., Cikala M., Stiening B., Käsbauer T., Zenner G., Popp T., Wagner A., Knapp R., Grunert M., Söding J., David C., and Huber A. The molecular cell death machinery in the simple cnidarian hydra includes an extended caspase family, APAF-1 and pro- and antiapoptotic Bcl-2 proteins. Cell Res. 20:812-825. (2010).

 

• Remmert M., Biegert A., Linke D., Lupas A. N., and Söding J. Evolution of outer membrane beta-barrels from an ancestral beta beta hairpin. Mol Biol Evol. 27:1348-1358 (2010).

 

• Alva V., Remmert M., Biegert A., Lupas A. N., and Söding J. A galaxy of folds. Protein Sci. 19:124-130 (2010).

 

• Biegert A. and Söding J.(invited) A boost for sequence searching.

G.I.T. Laboratory Journal 9-10:22-23 (2009). BIOforum Europe. 10:26-27 (2009).

 

• Hildebrand A., Remmert M., Biegert A., and Söding J. Fast and accurate automatic structure prediction with Hhpred. Proteins. 77 Suppl 9:128-132 (2009).

 

• Remmert M., Linke D., Lupas A. N. and Söding J. HHomp - Prediction and classification of outer membrane proteins. Nucleic Acids Res. 37:W446-451 (2009).

 

• Biegert A. and Söding J. Sequence context-specific profiles for homology searching. Proc Natl Acad Sci USA 106:3770-5 (2009).

 

• Bateman A., Finn R. D., Sims P. J., Wiedmer T., Biegert A., and Söding J. Phospholipid scramblases and Tubby like proteins belong to a new superfamily of membrane tethered transcription factors. Bioinformatics 25:159-162 (2009).