This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.
What is chemical genetics?
Chemical genetics is the study of small, chemical compounds and their effects on cellular targets. Through chemical genetics approaches, scientists will introduce cells to small-molecule libraries, or a small collection of chemical compounds, and screen for various phenotypes or cellular changes. In doing so, scientists are able to determine the effect that small molecules may have on a particular protein or gene of interest. An example of a basic chemical genetics approach can be seen in Figure 1 [1].
By designing small molecules that target specific cellular targets, scientists can ultimately elucidate changes in various biological pathways or molecular processes. This makes the use chemical genetics a crucial component of drug discovery and the development of various therapeutics. [2].
By designing small molecules that target specific cellular targets, scientists can ultimately elucidate changes in various biological pathways or molecular processes. This makes the use chemical genetics a crucial component of drug discovery and the development of various therapeutics. [2].
Chemical genetics and DM2: How does it fit together?
As mentioned above, chemical genetics is an approach used by scientists to identify the cellular targets of various molecules. Due to the creation of small-molecule libraries, molecules can be screened against cells at an extraordinarily high-throughput. Thus, before implementing a chemical genetics approach in the lab, scientists can check websites like PubChem, which is an open chemistry database sponsored by the NIH. The database contains comprehensive information various chemical structures, biological activities, safety, and cellular targets.
Through conducting a search under the "Targets" portion of the site for chemicals that have been found to influence CNBP activity, it was found that no viable chemical effectors for CNBP are listed in the database. This therefore constitutes a major gap in knowledge when it comes to CNBP and myotonic dystrophy type 2 (DM2), as there is currently no cure or viable therapeutic for the disease [3].
When searching "myotonic dystrophy" under the "Bioassays" portion of the website, however, 46 results were returned, with many of the results focusing on elimination of the extended toxic CNBP pre-mRNA transcripts that arise in individuals with DM2. These toxic pre-mRNA transcripts sequester cellular proteins and create protein clumping within the cell, which in turn leads to a whole host of devastating effects for the cell and individual. This therefore makes the extended CNBP pre-mRNA transcripts found within DM2 individuals a key area for future chemical genetics screens.
Through conducting a search under the "Targets" portion of the site for chemicals that have been found to influence CNBP activity, it was found that no viable chemical effectors for CNBP are listed in the database. This therefore constitutes a major gap in knowledge when it comes to CNBP and myotonic dystrophy type 2 (DM2), as there is currently no cure or viable therapeutic for the disease [3].
When searching "myotonic dystrophy" under the "Bioassays" portion of the website, however, 46 results were returned, with many of the results focusing on elimination of the extended toxic CNBP pre-mRNA transcripts that arise in individuals with DM2. These toxic pre-mRNA transcripts sequester cellular proteins and create protein clumping within the cell, which in turn leads to a whole host of devastating effects for the cell and individual. This therefore makes the extended CNBP pre-mRNA transcripts found within DM2 individuals a key area for future chemical genetics screens.
Discussion
In summary, chemical genetics is a way to affect cellular targets and there resulting biological pathways via the use of small molecules. Chemical genetics approaches are high-throughput methods that allow scientists to screen a wide variety molecules in a very short amount of time. A simple search of the PubChem database showed that there doesn't seem to be any small molecules that specifically affect the function of CNBP, but there is a small amount of literature on the effects of small molecules on the removal of mutated CNBP pre-mRNA transcripts. Ultimately, chemical genetics as it pertains to DM2 has not been heavily researched to date, but may prove to be crucial later on in the development of drugs to help DM2 patients with symptoms such as myotonia and restoration of muscle function.
References
- Cacace, E., Kritikos, G. & Typas, A. Chemical genetics in drug discovery. Curr. Op. Syst. Biol. 4, 35–42 (2017)
- Kawasumi, M.; Nghiem, P. Chemical genetics: elucidating biological systems with small-molecule compounds J. Invest. Dermatol. 2007, 127, 1577– 1584 DOI: 10.1038/sj.jid.5700853
- Meola, G., & Cardani, R. (2017). Myotonic dystrophy type 2 and modifier genes: An update on clinical and pathomolecular aspects. Neurological Sciences, 38(4), 535-546. doi:10.1007/s10072-016-2805-5
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