Scott Barolo Ph.D.
| 5732 Med Sci 2 |
| Ann Arbor, MI 48109 |
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DNA sequences called cis-regulatory elements, or enhancers, can be located upstream, downstream, internally, or tens of kilobases away from the genes they regulate. They determine when, where, and how strongly the gene will be expressed. Enhancers contain binding sites for transcription factors--proteins that bind DNA and turn genes on or off. A few highly conserved cell signaling pathways (e.g. Hedgehog, Wnt, Notch, TGF-beta, Jak/STAT, nuclear hormone, RTK/Ras/MAPK) control the vast majority of cell fate decisions during animal development. The primary effects of cell signaling are changes in gene expression, mediated by signal-regulated transcription factors. These factors bind to the enhancers of target genes, and turn them on or off in response to pathway signaling. Faulty signaling can result in diseases such as cancer, diabetes, autoimmune disorders, and neurodegenerative diseases, as well as developmental defects.
Signal-regulated enhancers have been intensively studied for years, but basic questions about these regulatory sequences remain unanswered. The gaps in our knowledge are best illustrated by the fact that "synthetic" versions of well-characterized enhancers (i.e., combinations of the known transcription factor binding sites) nearly always fail to drive gene expression in vivo. Therefore, it seems that we don't yet know all of the component parts of the enhancer, or its basic structure. These experiments raise the possibility that unidentified DNA-binding proteins, which may be functionally distinct from transcription factors, are essential for gene activation in higher eukaryotes. Are such proteins enhancer competence factors. How do these proteins interact with signal-regulated transcription factors to activate transcription?
Our goal is to define the component parts and molecular organization of the signal-regulated enhancer, by (1) identifying novel DNA-binding proteins required for enhancer function and (2) discovering the rules by which enhancer-binding proteins interact to promote (or inhibit) target gene activation in vivo. Using the Drosophila model system, we are employing biochemical, genetic, bioinformatic, evolutionary, and transgenic approaches to the study of these problems
Barolo, S., Castro, B., and Posakony, J.W. (2004.) New Drosophila transgenic reporters: Insulated P element vectors expressing fast-maturing RFP. BioTechniques 36: 436-440.
Barolo, S., Stone, T., Bang, A.G., and Posakony, J.W. (2002.) Hairless acts as an adaptor which recruits the corepressors Groucho and CtBP to Suppressor of Hairless. Genes & Development 16: 1964-1976.
Barolo, S. and Posakony, J.W. (2002.) Three habits of highly effective signaling pathways: Principles of transcriptional control by developmental cell signaling. Genes & Development 16: 1167-1181.
Barolo, S., Walker, R.G., Polyanovsky, A., Freschi, G., Keil, T., and Posakony, J.W. (2000.) A Notch-independent activity of Suppressor of Hairless is required for normal mechanoreceptor physiology. Cell 103: 957-969.
Barolo, S., Carver, L. A., and Posakony, J.W. (2000.) GFP and galactosidase transformation vectors for promoter/enhancer analysis in Drosophila. BioTechniques 29: 726-732.
Nibu, Y., Zhang, H., Bajor, E., Barolo, S. , Small, S., and Levine, M. (1998.) dCtBP mediates transcriptional repression by Knirps, Krppel and Snail in the Drosophila embryo. EMBO J. 17: 7009-7020.
Barolo, S. and Levine, M. (1997.) Hairy mediates dominant repression in the Drosophila embryo. EMBO J. 16: 2883-2981.
Zhou, J., Barolo, S., Szymanski, P., and Levine, M. (1996.) The Fab-7 element of the Bithorax complex attenuates enhancer-promoter interactions in the Drosophila embryo. Genes & Development 10: 3195-3201.
Arnosti, D., Gray, S., Barolo, S., Zhou, J., and Levine, M. (1996.) The gap protein Knirps mediates both quenching and direct repression in the Drosophila embryo. EMBO J. 15: 3659-3666.
Arnosti, D., Barolo, S., Levine, M., and Small, S. (1996.) The eve stripe 2 enhancer employs multiple modes of transcriptional synergy. Development 122: 205-214.
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