This web page was produced as an assignment for Genetics 564, an undergraduate course at UW-Madison.
Chemical Genetics
According to the tutorial review, "Chemical Genetics," chemical genetics can be defined as the study of biological systems using small molecule tools [1]. We can use chemical genetics as a tool to indirectly study a gene's role by altering the function of its protein. This can be accomplished by using small antagonist molecules that have a similar effect to a gene knockout [2]. There are two chemical genetic approaches: forward and reverse. Forward chemical genetics introduces a collection of unbiased compounds and screens for inhibition or stimulation of a protein. It's goal is to identify the protein(s) that interact which an introduced compound. Reverse chemical genetics begins with a known protein that is screened against a library of known compounds with a goal of identifying ligands that stimulate or inhibit the protein. The resulting phenotype from the altered protein is then studied [2].
For my chemical genetics research, I used the online database, Comparative Toxicogenomics Database. A search for the PER2 gene yielded a list of 120 interacting chemicals. A few chemicals of interest can be found below. The complete list of interacting chemicals can be found on the CTD website here.
Analysis
The small molecules listed above have interesting implications for depression and its research. Most notable to me are the environmental factors that influence PER2 expression such as air pollution, dietary fats, ozone, and smoke. Other chemicals include drugs--some more surprising than others. I am not surprised by acetaminophen, cocaine, melatonin, methamphetamine, or morphine, as these drugs all target the brain. Estradiol stands out, but it hard to gauge its importance as it has mixed effects.
The environmental factors are important to note in relation to depression and bring to light many questions. Can we change our mood by changing our diets? Do people living among environmental toxins exhibit higher rates of depression? What about people who smoke? Does smoking cause depression, or are people with depression more likely to smoke? How does climate change and ozone levels in the atmosphere affect instances of depression?
Lastly, I would like to comment on cocaine's role in depression. Recent studies have indicated a role for circadian genes in drug addiction [3]. These genes are expressed outside of the suprachiasmatic nucleus (SCN), which is involved in regulating the circadian rhythm and is a major region where PER2 is expressed. Clinical addiction is defined by compulsive drug use, which enacts long-lasting changes to the brain that are not easily reversed. Major regions that are affected are involved in the dopaminergic pathways in the brain, which are involved with reward and pleasure processes [3]. PER2 itself has been implicated in cocaine addiction. A new variation (specifically a variable number tandem repeat polymorphism (VNTR)) has been found in the third intron of the PER2 gene. This variation has been linked to vulnerability for cocaine addiction as cocaine abusers consistently share the characteristic of low levels of D2 dopamine receptors in the striatum of the brain [4]. Cocaine addicts may abuse cocaine because it increases their levels of dopamine receptors by interacting with PER2. Future research is warranted to elude the consequences of the chemicals presented here on depression and the brain in general.
The environmental factors are important to note in relation to depression and bring to light many questions. Can we change our mood by changing our diets? Do people living among environmental toxins exhibit higher rates of depression? What about people who smoke? Does smoking cause depression, or are people with depression more likely to smoke? How does climate change and ozone levels in the atmosphere affect instances of depression?
Lastly, I would like to comment on cocaine's role in depression. Recent studies have indicated a role for circadian genes in drug addiction [3]. These genes are expressed outside of the suprachiasmatic nucleus (SCN), which is involved in regulating the circadian rhythm and is a major region where PER2 is expressed. Clinical addiction is defined by compulsive drug use, which enacts long-lasting changes to the brain that are not easily reversed. Major regions that are affected are involved in the dopaminergic pathways in the brain, which are involved with reward and pleasure processes [3]. PER2 itself has been implicated in cocaine addiction. A new variation (specifically a variable number tandem repeat polymorphism (VNTR)) has been found in the third intron of the PER2 gene. This variation has been linked to vulnerability for cocaine addiction as cocaine abusers consistently share the characteristic of low levels of D2 dopamine receptors in the striatum of the brain [4]. Cocaine addicts may abuse cocaine because it increases their levels of dopamine receptors by interacting with PER2. Future research is warranted to elude the consequences of the chemicals presented here on depression and the brain in general.
References
[1] O'Connor, C.J., Laraia L., and Spring, D.R. (2011). Chemical genetics. Chem. Soc. Rev. 40(8): 4332-45. doi: 10.1039/c1cs15053g.
[2] Walsh, D. and Chang, Y-T. (2006). Chemical genetics. Chem. Rev. 106: 2476-2530.
[3] Edgardo, F. and McClung, C. (2009). A role for the circadian genes in drug addiction. Neuropharm. 56(1): 91-96. doi:10.1016/j.neuropharm.2008.06.054
[4] Shumay, E. et al. (2012). Repeat variation in the human PER2 gene as a new genetic marker associated with cocaine addiction and brain dopamine D2 receptor availability. Transl. Psychiatry 2(e86). doi: 10.1038/t-.2012.11.
[1] O'Connor, C.J., Laraia L., and Spring, D.R. (2011). Chemical genetics. Chem. Soc. Rev. 40(8): 4332-45. doi: 10.1039/c1cs15053g.
[2] Walsh, D. and Chang, Y-T. (2006). Chemical genetics. Chem. Rev. 106: 2476-2530.
[3] Edgardo, F. and McClung, C. (2009). A role for the circadian genes in drug addiction. Neuropharm. 56(1): 91-96. doi:10.1016/j.neuropharm.2008.06.054
[4] Shumay, E. et al. (2012). Repeat variation in the human PER2 gene as a new genetic marker associated with cocaine addiction and brain dopamine D2 receptor availability. Transl. Psychiatry 2(e86). doi: 10.1038/t-.2012.11.