What is chemical genomics?
Simply put, chemical genomics is the study of how small molecules can perturb biological pathways. Through genetic screens, small molecules that impact the biological processes being studied can help understand the exact biochemical relationships that are present in the biological pathways involved [1]. These small molecules can be introduced to specific tissue samples, or throughout the whole organism. Chemical genomics is especially useful because it can simultaneously identify relevant target pathways and novel therapeutic drugs for a particular disease or phenotype you are studying.
How would you use chemical genomics?
Using zebrafish as a model organism, a chemical genetics screen can be conducted in wild-type and DYRK1A mutants to see if small molecules can rescue the neural cell proliferation in mutant zebrafish. The first step in setting up a chemical genetics screen is choosing the type of chemical library you will expose to your model organism groups. A diversity-oriented library will use chemicals that can target a diverse structures while a focused library will target similar structures [2]. A diversity-oriented is especially useful when the exact protein structures in a biological pathway is not well-characterized. The next step is to expose the experimental groups with the chemicals and observe for relevant phenotypes. A mutant with rescued phenotypes is a "chemical hit" and the small molecule/chemical that resulted in this hit could pave the way for a novel drug for targeting the disease of interest. Further assays that study the specificity and efficacy of the small molecule would have to be done.
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Discussion
There are not many chemical genomic studies that pertain to DYRK1A, and there is not readily-available knowledge of the types of chemicals that could interact with DYRK1A. Because of the presence of DYRK1A in various tissue types, and its several known functions and targets within cells, it is difficult to predict a viable chemical library to set up a genetic chemical screen to target DYRK1A mutants. Preliminary studies that elucidate the chemical interactions that DYRK1A can have will help pave the way for future chemical genomics studies of DYRK1A. This will ultimately result in novel findings of small molecules that can perturb the DYRK1A, and perhaps even lead to novel drug therapies to prevent the neurodegenerative effects of DYRK1A.
References
[1] Florian, S., Hümmer, S., Catarinella, M., & Mayer, T. U. (2007). Chemical genetics: reshaping biology through chemistry. HFSP journal, 1(2), 104–114. doi:10.2976/1.2752600
[2] Dang M, Fogley R, Zon LI (2016) Identifying novel cancer therapies using chemical genetics and zebrafish. Adv Exp Med Biol 916:103–124
[2] Dang M, Fogley R, Zon LI (2016) Identifying novel cancer therapies using chemical genetics and zebrafish. Adv Exp Med Biol 916:103–124
This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.