Prof. Andreas Hecht
Prof. Andreas Hecht
Institute of Molecular Medicine and Cell Research
University of Freiburg
Cellular differentiation and control of gene expression - harnessing the power of signal transduction cascades
What makes the difference between a neuron and a hepatocyte, a myoblast and a lymphocyte, a healthy intestinal epithelial cell and a colorectal cancer cell? Ultimately, all cellular properties are determined by the selective induction and repression of specific groups of genes in response to extracellular signals. Surprisingly, nature employs only a few growth factor families and a small number of effector molecules to orchestrate the most complex patterns of gene expression. The recurrent use of this limited set of signal transducers in a diversity of contexts leads to a fundamental problem: How can the same players control different target genes in different cells? Which are the mechanisms underlying differential gene regulation?
To address these questions our research is focused on the Wnt/β-catenin signal transduction pathway in which β-catenin and members of the T-cell factor/Lymphoid enhancer factor (TCF/LEF) family of DNA-binding proteins control the expression of numerous genes which are involved in such diverse processes as proliferation, differentiation, patterning, morphogenesis, and apoptosis. Deregulation of Wnt signalling is seen in various forms of human disease, most notably colorectal cancer. In a mouse developmental model system we investigate molecular mechanisms which permit or prevent access of the Wnt pathway to its target genes in a stage and tissue-specific manner. In a human tumour cell model we ask how expression of certain tumour suppressors can be uncoupled from regulation by the Wnt pathway – a process which appears to promote tumour progression and leads to a worsening of the disease. For our studies we use cell biology techniques, molecular genetics, genomics and proteomics approaches to study functional properties of TCF/LEF transcription factors and to gain insight into the importance of chromatin structure and epigenetic processes as sorting mechanisms for gene expression and pathway accessibility. In the long run, our studies will improve the understanding of molecular mechanisms underlying differential regulation of gene expression during cellular differentiation and in pathological situations.
10 selected publications
- SNAIL1-mediated downregulation of FOXA proteins facilitates the inactivation of transcriptional enhancer elements at key epithelial genes in colorectal cancer cells.
Jägle S, Busch H, Freihen V, Beyes S, Schrempp M, Boerries M, Hecht A (2017).
PLoS Genet 13, e1007109.
- Enhancer decommissioning by Snail1-induced competitive displacement of TCF7L2 and down-regulation of transcriptional activators results in EPHB2 silencing.
Schnappauf O, Beyes S, Dertmann A, Freihen V, Frey P, Jägle S, Rose K, Michoel T, Grosschedl R, Hecht A (2016).
Biochim Biophys Acta 1859, 1353-1367.
- SNAIL1 combines competitive displacement of ASCL2 and epigenetic mechanisms to rapidly silence the EPHB3 tumor suppressor in colorectal cancer.
Rönsch K, Jägle S, Rose K, Seidl M, Baumgartner F, Freihen V, Yousaf A, Metzger E, Lassmann S, Schüle R, Zeiser R, Michoel T, Hecht A (2015).
Mol Oncol 9, 335-354.
- Silencing of the EPHB3 tumor-suppressor gene in human colorectal cancer through decommissioning of a transcriptional enhancer.
Jägle S, Rönsch K, Timme S, Andrlova H, Bertrand M, Jäger M, Proske A, Schrempp M, Yousaf A, Michoel T, Zeiser R, Werner M, Lassmann S, Hecht A (2014).
Proc Natl Acad Sci U S A 111, 4886-4891.
- Intrinsic properties of Tcf1 and Tcf4 splice variants determine cell-type-specific Wnt/beta-catenin target gene expression.
Wallmen B, Schrempp M, Hecht A (2012).
Nucleic Acids Res 40, 9455-9469.
- Class I and III HDACs and loss of active chromatin features contribute to epigenetic silencing of CDX1 and EPHB tumor suppressor genes in colorectal cancer.
Rönsch K, Jäger M, Schöpflin A, Danciu M, Lassmann S, Hecht A (2011).
Epigenetics 6, 610-622.
- Alternative splicing of Tcf7l2 transcripts generates protein variants with differential promoter-binding and transcriptional activation properties at Wnt/beta-catenin targets.
Weise A, Bruser K, Elfert S, Wallmen B, Wittel Y, Wöhrle S, Hecht A (2010).
Nucleic Acids Res 38, 1964-1981.
- Differential control of Wnt target genes involves epigenetic mechanisms and selective promoter occupancy by T-cell factors.
Wöhrle S, Wallmen B, Hecht A (2007).
Mol Cell Biol 27, 8164-8177.
- Control over Wnt target gene expression.
Hecht A, Kemler R (2000).
EMBO Rep 1, 24-28.
- he p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates.
Hecht A, Vleminckx K, Stemmler MP, van Roy F, Kemler R (2000).
T EMBO J 19, 1839-1850.