Gene regulation analysis by the zebrafish model system

Despite enormous progress in our understanding of the basic mechanisms of transcription regulation, the sequence of the human genome provides little clues about the codes that control genes to respond to signals and to function in characteristic patterns. Therefore, mapping and identifying cis-regulatory mutations associated with congenital and multifactorial disease remains a challenge of the post-genomic era. To add to the challenge the “grammar” of how multiple transcription factors act on complex CRMs is poorly understood. Elucidation of these codes will allow us to predict function and pattern of gene expression from sequence information and in mapping cis-regulatory mutations. The zebrafish (Danio rerio) represents an excellent model to elucidate the regulatory architecture of vertebrate genomes for the following: i.) The transcriptional regulatory mechanisms show remarkable similarity with mammals; ii.) The genome sequence permits computational predictions; iii) Fast functional analysis tools for CRMs have been developed; iv.) Numerous mutants and morphant phenotypes for transcription factor genes are available; v.) Zebrafish is a low cost vertebrate model. In our research programme, we exploit the zebrafish model system in a complementary set of approaches, including embryological methods (mutant and morphant analysis), chromatin immunoprecipitation, transgenic tools, as well as bioinformatics including comparative genomics.

1.Differential gene regulation by promoter recognition proteins in the vertebrate embryo - The biological function of the TATA binding protein family during early embryo development - Core promoter structure and regulation in differential gene expression - TBP associated factors (TAFs) in development and disease

2. Cis–regulatory codes of developmental gene expression - Identification and functional characterisation of developmental cis regulatory modules (CRMs) - Promoter-enhancer interaction specificity analysis - high throughput analysis of CRM function by automated imaging of zebrafish embryos

3. The application of zebrafish as a functional genomic model to study the genetic basis of human disease - Birt-Hogg-Dube, ARC and Martsolf syndromes (in collaboration with the Maher, Gissen and Aligianis groups)

Lab Members

Current
Dr Yavor Hadzhiev, Post Doc
Jochen Gehrig, PhD student
Andreas Zaucker, PhD student
Jenny Roberts, PhD student
Mathew Rawlings, Research Technician
Past
Marco Ferg, PhD 2008
Eva Kalmar, PhD pending
Chengyi Song
Dr Agnes Lovas
Carolin Balduf
Stephanie Wiessner
Martin Habacher
Simone Schindler

Selected Publications

1. Koenig, H., Matter, N., Bader, R., Thiele, W. and Müller, F. (2007) Splicing segregation: the minor spliceosome acts outside the nucleus and controls cell proliferation Cell, 131(4):718-29.
2. Ferg, M., Sanges, R., Gehrig, J., Lovas, A., Bauer, M., Kiss, J., Szabo, M., Olasz, F., Pankratz, M., Stupka, E., and Müller, F. (2007) The TATA binding protein (TBP) regulates maternal mRNA degradation and differential zygotic gene activation in the zebrafish embryo. EMBO J. 26(17) 3945-56
3. Hadzhiev, Y., Lang, M., Ertzer, R., Meyer, A., Straehle, U. and Müller, F. (2007) Functional diversification of sonic hedgehog paralog enhancers identified by phylogenomic reconstruction. Genome Biol 8(6):R106.
4. Sanges, R., Kalmar, E., Claudiani, P., D'Amato, M., Müller, F*. and Stupka, E. (2006) Shuffling of cis-regulatory elements is a pervasive feature of the vertebrate lineage. Genome Biol, 7(7), R56
5. Bártfai, R., Balduf, C., Hilton, T., Rathmann, Y., Hadzhiev, Y., Tora, L., Orbán, L. and Müller, F. (2004) TBP2, a vertebrate-specific member of the TBP family is required in embryonic development of zebrafish. Curr. Biol, 14, 593-598.
6. Müller, F., Lakatos, L., Dantonel, J., Strahle, U, Tora, L. (2001) TBP is not universally required for zygotic RNA polymerase II transcription in zebrafish. Curr. Biol, 11(4), 282-7.