Enhancers (cis-regulatory elements) in development and evolution

Our research interests include:
Gene regulation and signal transduction in development;
Structure and function of transcriptional enhancers;
Enhancer evolution.

DNA sequences called cis-regulatory elements, or enhancers, can be located upstream or downstream of a gene, or even within it. They may be very near the promoters they regulate or many kilobases away--even on the far side of other genes. Enhancers control when, where, and how strongly genes will be expressed. They contain binding sites for transcription factors--proteins that bind DNA and turn genes on or off.

A few highly conserved cell signaling pathways, such as Notch, Wnt, Hedgehog, TGF-β/BMP, and RTK/Ras/MAPK, are essential for specifying a vast number of cell fates during embryonic development and adult stem cell function. These same pathways are central to many human diseases, most notably cancer, which is often caused by aberrant signaling.  

Signaling pathways affect cell fate primarily by altering the activity of transcription factors (TFs), which in turn control the expression of pathway target genes. Signal-regulated enhancers located near pathway target genes contain binding sites for signal-regulated TFs and for other, tissue- or cell-type-specific TFs; interactions among these factors determine the expression pattern of the target gene.

Very basic questions about biological patterning information and cis-regulatory logic 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. We are employing transgenic, genetic, biochemical, evolutionary, and bioinformatics approaches to the study of these problems.

We use the Drosophila model system because of its genetic advantages and the ease with which transgenic animals can be generated, but we are always focused on molecules and pathways with very highly conserved regulatory functions.

We are actively researching the following aspects of enhancer activity:
- In vivo structure-function studies of developmental enhancers
- Mechanisms of transcriptional regulation by the Hedgehog, Wnt, Notch, and MAPK pathways
- Rules of enhancer “grammar”
- In vivo quantitation and computational modeling of gene expression
Cis-regulatory sequence evolution
- Tissue-specific responses to highly pleiotropic signals
- Physical interactions among enhancers and promoters
- Reverse-engineering synthetic enhancer elements
-Other enhancery things you might find interesting

Send me an email (sbarolo@umich.edu) and we can talk about possible research projects in more detail.