The ability to sequence entire genomes and transcriptomes in ever shorter timeframes has far outpaced our understanding of how gene expression is controlled. Even though we have a firm knowledge of the general principles of gene expression, we are still far from a holistic and comprehensive understanding of the underlying regulation. It is one of the major challenges in modern biology to gain detailed understanding of the regulatory principles and networks that control gene expression.
In recent years, facilitated by new technology and the development of novel methods, evidence accumulated for a surprising discrepancy between the cellular transcriptome and the proteome in eukaryotic cells. Several large-scale datasets show only limited overlap between cellular mRNA abundance/diversity and the corresponding proteome. This appears to be based on differences in both protein synthesis- and decay-rates, with protein abundance being mostly controlled at the level of translation. These findings have fueled the hypothesis that translational regulation might play a role far more important than initially anticipated, fine tuning the levels of a many cellular proteins. However, our understanding of the basic principles and underlying mechanisms of regulation is still rather limited and we are just beginning to see the complexity of eukaryotic translation.
In the lab we are combining global, systems-biology approaches with reductionist, mechanistic experimentation to gain a deeper understanding of translational control.
Information about the individual projects can be found here:
- Regulation of translation during the unfolded proteon response (UPR)
- Translational Control by the Drosophila RNA-binding protein Sex Lethal (SXL)
- Translational control via protein-regulated upstream open reading frames
- SXL in translational repression of nanos mRNA
- Sister of Sex Lethal – a novel translation repressor protein from Drosophila
We are extremely grateful for the generous support that we receive from a number of funding agencies! Without this support we would not be able to pursue our work and to experimentally address intriguing biological questions.
Science is a community effort! We are very happy about our collaborations with the following labs (alphabetical order):
Albrecht Bindereif, Institute of Biochemistry, Justus-Liebig-University Giessen, Germany
Benedikt Beckmann, Integrative Research Institute (IRI) for the Life Sciences, Humboldt Universität, Berlin, Germany
Björn Tews, previously at the German Cancer Research Center (DKFZ), Heidelberg, Germany, now at AbbVie
Fatima Gebauer, Centre for Genomic Regulation (CRG) , Barcelona, Spain
Grischa Tödt, Structural and Computational Biology, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
Oliver Rossbach, Institute of Biochemistry, Justus-Liebig-University Giessen, Germany
Robert Ahrends, Leibniz-Institute for Analytical Sciences (ISAS), Dortmund, Germany
Sebastian Glatt, Max Planck Research Group at the Malopolska Centre of Biotechnology/Jagiellonian University, Krakow, Poland
Müller-McNicoll M, Rossbach O, Hui J, and Medenbach J: Auto-regulatory feedback by RNA-binding proteins – accepted for publication at the Journal of Molecular Cell Biology
Urdaneta EC, Vieira C , Hick T, Wessels HH, Moschall R, Medenbach J, Ohler U, Granneman S, Selbach M, and Beckmann BM: Purification of Cross-linked RNA-Protein Complexes by Phenol-Toluol Extraction. Nat Commun, 2019, 1;10(1):990
Moschall R, Rass M, Rossbach O, Lehmann G, Kullmann L, Eichner N, Strauss D, Meister G, Schneuwly S, Krahn M, and Medenbach J: Sister of Sex-lethal antagonizes Sxl-dependent alternative splicing to maintain a male-specific gene expression pattern in Drosophila Nucleic Acids Res. Nucleic Acids Res., 2019, 18;47(5):2276-2288
Moschall R, Strauss D, Garcia-Beyaert M, Geabuer F, Medenbach J: Drosophila Sister-of-Sex-lethal is a repressor of translation. RNA, 2018, 24:149-58
Knüppel R, Christensen RH, Gray FC, Esser D, Strauß D, Medenbach J, Siebers B, MacNeill SA, LaRonde N, Ferreira-Cerca S: Insights into the evolutionary conserved regulation of Rio ATPase activity. Nucleic Acids Res. 2017 [Epub ahead of print]
Moschall R, Gaik M, Medenbach J.: Promiscuity in post-transcriptional control of gene expression: Drosophila Sex-lethal and its regulatory partnerships. FEBS Lett. 2017 doi: 10.1002/1873-3468.12652.
Schneider, T., Hung, L-S., Schreiner, S., Starke, S., Eckhof, H., Rossbach, O., Reich, S., Medenbach, J., and Bindereif, A.: CircRNA-protein complexes: IMP3 protein component defined subfamily of circRNPs. Scientific Reports, 2016, 6(31313).
Beckmann, BM., Castello, A., and Medenbach, J.: The expanding universe of ribonucleoproteins: of novel RNA-binding proteins and unconventional interactions. Pflugers Arch., 2016,468(6):1029-40.
Medenbach, J., Seiler, M., and Hentze, MW.: Translational control via protein-regulated upstream open reading frames. Cell, 2011, 145(6):902-13.
– Featured in: Yao P. and Fox PL: Sex lethal and upstream ORFs: a bait-and-trap system for ribosomes. Genome Biology, 2011, 12:121.
– Featured in Faculty of 1000
Rösel, TD.1, Hung, LH.1, Medenbach, J.1, Donde, K., Starke, S., Benes, V., Rätsch, G., and Bindereif, A.: RNA-Seq analysis in mutant zebrafish reveals role of U1c protein in alternative splicing regulation. EMBO Journal, 2011, 30(10):1965-76. (1 these authors contributed equally)
Pérard, J., Rasia, R., Medenbach, J., Ayala, I., Boisbouvier, J., Drouet, E., and Baudin, F.: Human initiation factor eIF3 subunit binteracts with HCV IRES RNA through its N-terminal RNA recognition motif. FEBS Lett., 2009, 583(1): 70-4.
Medenbach, J.1, Licht, K.1, Lührmann, R., Kambach, C., and Bindereif, A.: 3‘-cyclic phosphorylation of U6 snRNA leads to recruitment of recycling factor p110 through LSm proteins. RNA, 2008, 4(8): 1532-8. (1 these authors contributed equally)
Medenbach, J.1,Trede1, N.S., Damianov1, A., Hung, L.-H., Weber, G.J., Paw, B.H., Zhou, Y., Hersey, C., Zapata, A., Keefe, M., Barut, B.A., Stuart, A.B., Katz, T., Amemiya, C.T., Zon, L.I., and Bindereif, A.: Network of coregulated spliceosome components revealed by zebrafish mutant in recycling factor p110. Proc. Natl. Acad. Sci. USA, 2007, 104(16): 6608-13. (1 these authors contributed equally)
Medenbach, J., Schreiner, S., Liu, S., Lührmann, R., and Bindereif, A.: Human U4/U6 snRNP Recycling Factor p110: Mutational Analysis Reveals the Function of the Tetratricopeptide Repeat Domain in Recycling”, Molecular and Cellular Biology, 2005, 24(17): 7392-7401.
Medenbach, J., Damianov, A., Schreiner, S., and Bindereif, A.: Sedimentation Analysis of Ribonucleoprotein Complexes. Handbook of RNA Biochemistry, 2005, R. K. Hartmann, A. Bindereif, A. Schön and E. Westhof. Weinheim, Wiley-VCH. 1: 428-437.