Prof. Dr. Michael Kracht, M.D.
Justus Liebig University Giessen, Biomedical Research Centre (BFS)
Rudolf-Buchheim-Institute of Pharmacology
Topics of our group
Chronic inflammatory conditions (such as rheumatoid arthritis, psoriasis or inflammatory bowel disease) affect around 10% of people worldwide. Currently, many new therapies are being introduced such as JAK protein kinase inhibitors or monoclonal antibodies directed at cytokines, but there is still no cure. We follow the idea that recurrent episodes of inflammation are caused by aberrant rewiring of both, signaling pathways and formation of messenger-ribonucleoprotein particles (mRNPs) rather than by defined genetic mutations. Thus, our research is focused on identifying the components and regulatory mechanisms of as yet hypothetical “inflammatory” mRNPs that confer signals of gene expression and determine the inflammatory proteome in time and space. For this, we apply multiple state-of-the art biochemical, molecular biology, cell biology and bioinformatics methods including various forms of (epi)genome editing by the CRISPR-Cas9 system. As major biological models we use human epithelial cells which cover the inner and outer linings of our body and thus provide a crucial part of the innate immune response. During inflammation these cells rapidly synthesize and secrete cytokines such as interleukin(IL)-1 and chemokines. Together, these factors control both, activation and migration of infiltrating and resident tissue cells. Contrary to the prevailing view we postulate that the cytokine response is initially primarily controlled by specific processes occurring within the chromatin rather than by cytosolic signaling pathways. Hence, a current focus is the analysis of the composition of nuclear mRNPs which are assembled within so called transcription factories. But we also investigate how mRNPs are remodeled when they travel to the cytoplasm and become translated following the idea that gene expression is not simply a linear process but involves multiple levels of feedback control and buffering of mRNA versus protein levels (1). As an example, we recently found that targeted mutations of strong inflammatory enhancers not only suppressed transcriptional processes but also affected the inflammatory secretome (2). To explore these phenomena further we apply a broad range of single cell analyses to study transcriptional bursting, RNA polymerase II recruitment and transcriptional elongation. We also investigate post-transcriptional gene regulation including mRNA decay and protein de novo synthesis. All of our projects are embedded within a highly active and experienced working group. This environment facilitates multiple social and scientific interactions as well as the (rapid) acquirement of a broad repertoire of scientific methods and concepts in order to achieve high-ranking first author publications during the PhD or PostDoc work. As new members for our lab we are seeking scientists who successfully finished university degrees in medicine, biochemistry, biology or a related field and who share a specific interest in mechanistically oriented basic medical research, biochemistry, cell biology, molecular imaging and molecular biology.
For further details see: http://www.uni-giessen.de/faculties/f11/facilities/rbi-en/research/ and please read the following publications References:
1. Zarnack K, Balasubramanian S, Gantier MP, Kunetsky V, Kracht M, Schmitz ML, Sträßer K. 2020. Dynamic mRNP Remodeling in Response to Internal and External Stimuli. Biomolecules 10. https://doi.org/10.3390/biom10091310
2. Weiterer SS, Meier-Soelch J, Georgomanolis T, Mizi A, Beyerlein A, Weiser H, ....., Kracht M. 2020. Distinct IL-1alpha-responsive enhancers promote acute and coordinated changes in chromatin topology in a hierarchical manner. EMBO J 39:e101533. https://doi.org/10.15252/embj.2019101533
3. Mayr-Buro C, Schlereth E, Beuerlein K, Tenekeci U, Meier-Soelch J, Schmitz ML, Kracht M. 2019. Single-Cell Analysis of Multiple Steps of Dynamic NF-kappaB Regulation in Interleukin-1alpha-Triggered Tumor Cells Using Proximity Ligation Assays. Cancers (Basel) 11. https://doi.org/10.3390/cancers11081199
4. Meier-Soelch J, Jurida L, Weber A, Newel D, Kim J, Braun T, ....., Kracht M. 2018. RNAi-Based Identification of Gene-Specific Nuclear Cofactor Networks Regulating Interleukin-1 Target Genes. Frontiers in Immunology 9. https://doi.org/ARTN 775 10.3389/fimmu.2018.00775
5. Schmitz ML, Shaban MS, Albert BV, Gokcen A, Kracht M. 2018. The Crosstalk of Endoplasmic Reticulum (ER) Stress Pathways with NF-kappaB: Complex Mechanisms Relevant for Cancer, Inflammation and Infection. Biomedicines 6. https://doi.org/10.3390/biomedicines6020058
6. Poppe M, Wittig S, Jurida L, Bartkuhn M, Wilhelm J, Muller H, ....., Kracht M. 2017. The NF-kappaB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells. PLoS Pathog 13:e1006286. https://doi.org/10.1371/journal.ppat.1006286
7. Schmitz ML, Kracht M. 2016. Cyclin-Dependent Kinases as Coregulators of Inflammatory Gene Expression. Trends Pharmacol Sci 37:101-13. https://doi.org/10.1016/j.tips.2015.10.004
8. Tenekeci U, Poppe M, Beuerlein K, Buro C, Muller H, Weiser H, ....., Kracht M. 2016. K63-Ubiquitylation and TRAF6 Pathways Regulate Mammalian P-Body Formation and mRNA Decapping. Mol Cell 62:943-57. https://doi.org/10.1016/j.molcel.2016.05.017
9. Jurida L, Soelch J, Bartkuhn M, Handschick K, Muller H, Newel D, ....., Kracht M. 2015. The Activation of IL-1-Induced Enhancers Depends on TAK1 Kinase Activity and NF-kappaB p65. Cell Rep 10:726-739. https://doi.org/10.1016/j.celrep.2015.01.001
10. Handschick K, Beuerlein K, Jurida L, Bartkuhn M, Muller H, Soelch J, ....., Kracht M. 2014. Cyclin-dependent kinase 6 is a chromatin-bound cofactor for NF-kappaB-dependent gene expression. Mol Cell 53:193-208. https://doi.org/10.1016/j.molcel.2013.12.002
11. Ziesche E, Kettner-Buhrow D, Weber A, Wittwer T, Jurida L, Soelch J, ....., Kracht M. 2013. The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-kappaB. Nucleic Acids Res 41:90-109. https://doi.org/10.1093/nar/gks916
12. Rzeczkowski K, Beuerlein K, Muller H, Dittrich-Breiholz O, Schneider H, Kettner-Buhrow D, ....., Kracht M. 2011. c-Jun N-terminal kinase phosphorylates DCP1a to control formation of P bodies. J Cell Biol 194:581-96. https://doi.org/10.1083/jcb.201006089
13. Weber A, Wasiliew P, Kracht M. 2010. Interleukin-1 (IL-1) pathway. SciSignal 3:cm1.
14. Gaestel M, Kotlyarov A, Kracht M. 2009. Targeting innate immunity protein kinase signalling in inflammation. Nat Rev Drug Discov 8:480-99. https://doi.org/10.1038/nrd2829