As the cells in an embryo grow and divide, they must adopt different fates to generate complex structures and tissues with different cell types. Extracellular signals play a key role in triggering cells to adopt different fates, but surprisingly there are only a handful of extracellular signals that get used over and over again at different times and places during development.
For example, in mammalian development, the Wnt signaling pathway is important for inducing a group of cells form the intestine instead of the stomach and then later for inducing the intestine to form villi, the fingerlike projections that help absorb nutrients. Wnt signaling also plays key roles in the development of the brain, lung, liver, kidney, and many other tissues by activating the expression of different genes in these tissues.
In the Amanda Zacharias Lab, we are interested in understanding the mechanisms underlying how the Wnt signaling pathway has different effects on gene expression at different times and places—different contexts—during development. We are investigating this question using the nematode worm C. elegans as a model and are interested in translating our findings to vertebrate models, including stem cells.
Our lab is focused on the questions of how precise activation of the Wnt signaling pathway occurs, how the level of activation impacts target gene regulation, and how these mechanisms are integrated with other context regulators, such as transcription factors and chromatin modifiers, to activate target genes with precision and robustness. We are particularly motivated to understand how the response to a signal and other context regulators is encoded in the genome in the form of cis-regulatory elements, pieces of DNA that act as switches to turn gene expression on and off in the appropriate context.
Despite the wealth of genomic data produced by cis-regulatory element mapping projects, such as ENCODE, we do not yet understand cis-regulatory elements well enough to identify them or predict how they will regulate genes based on just their DNA sequence. Our goal is to understand how the Wnt pathway transcription factor, TCF, and its coactivator, β−catenin, interact with context transcription factors in cis-regulatory elements to regulate transcription in the appropriate context, and use these rules to identify Wnt target genes and predict their expression pattern from sequence alone.
Contact us if you are interested in joining our lab or learning more about our work.
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