This web page was produced as an assignment for Genetics 564, an undergraduate course at UW-Madison.
Genetic Motifs
DNA motifs are short, reoccurring sequence patterns that are presumed to have a biological function [1]. DNA motifs often indicate binding sites for proteins such as transcription factors and nucleases. Others are involved in RNA processes, such as ribosome binding and mRNA processing [1]. DNA motifs can be used to predict the function of resultant RNA or protein from that gene.
There are now online databases that can be used to discover genomic and proteomic motifs, as well as compare them between organisms. I used a website called MEME: Multiple Em for Motif Elicitation. I entered the genomic FASTA sequences of Homo sapiens, Arabadopsis thaliana, C. elegans, and Oryza Sativa (rice). Below are the three resultant motifs that I obtained from MEME. The height of the letters refer to the probability of finding that specific base at that location [2]. Some locations only have one letter, meaning that between the four organisms used here, they all have that same base in that location. For the locations that have more than one letter, the taller the letter is, the more common that letter is in the position among the species. For locations that have no letter, such as the second location in the second motif, that means that each of the four species was found to have a different base there.
There are now online databases that can be used to discover genomic and proteomic motifs, as well as compare them between organisms. I used a website called MEME: Multiple Em for Motif Elicitation. I entered the genomic FASTA sequences of Homo sapiens, Arabadopsis thaliana, C. elegans, and Oryza Sativa (rice). Below are the three resultant motifs that I obtained from MEME. The height of the letters refer to the probability of finding that specific base at that location [2]. Some locations only have one letter, meaning that between the four organisms used here, they all have that same base in that location. For the locations that have more than one letter, the taller the letter is, the more common that letter is in the position among the species. For locations that have no letter, such as the second location in the second motif, that means that each of the four species was found to have a different base there.
TOP3B Motifs
After finding these motifs from MEME, there are different steps you can take to further analyze the motifs (which can be done directly from MEME). I decided to enter my motifs into GOMO: Gene Ontology for Motifs. The purpose of GOMO is to identity possible roles (aka GO terms) for DNA binding motifs [3]. This makes this database prefect for TOP3B, as the best known function of the product of TOP3B, DNA topological change, involved DNA binding. After simply clicking the GOMO button on my MEME results page, GOMO presented me with a list of GO terms found to be significantly associated with the target genes (what TOP3B would bind to) of the motif [3]. Below is a list of GO terms found for each motif above. (BP=Biological Process, MF=Molecular Function).
Motif 1:
BP: G-protein coupled receptor protein signaling pathway BP: Immune Response BP: Regulation of cytokine production BP: Inflammatory response BP: Sensory perception of smell MF: Olfactory receptor activity |
Motif 2:
BP: Positive regulation of interleukin-2 biosynthetic process BP: Bacterium response BP: G-protein coupled receptor protein signaling pathway BP: Sensory perception of smell MF: Olfactory receptor activity |
Motif 3:
BP: G-protein coupled receptor protein signaling pathway BP: Sensory perception of smell MF: Olfactory receptor activity |
Analysis of TOP3B Motifs
These GOMO results can be used to discern pathways that TOP3β may affect. This could potentially indicate non-DNA binding partners for TOP3β--if TOP3β can bind to these DNA sequences then it could potentially bind their RNA products as well, and perhaps even their protein products. From the above results, it can be seen that TOP3β is associated with signaling pathways (G-protein coupled receptors, cytokines) as well as the immune response (immune response, inflammatory response). I was not overly surprised by these results after my research into TOP3B. Schizophrenia is a complex brain disorder, with symptoms relating to communication issues, learning issues, and the inability to discern real from imagined. It is very logical that faulty signaling could be the behind all of these symptoms. Thus, an association between TOP3β and signaling makes a lot of sense. Also, inflammation in the brain has been found in studies of schizophrenia [4]. So, again, this association is not shocking either. However, the association between TOP3B and the perception of smell did surprise me. After some thought, the perception of smell could be viewed as a specific form of signaling. Furthermore, the final destination of this signaling is the brain, an organ that directly relates to schizophrenia. Scents can produce emotional responses and cause the recall of vivid memories. Since some of the symptoms of schizophrenia are lacking (appropriate) emotional responses and hallucinations, perhaps this association between olfactory perception and schizophrenia is more important than I first thought. This could be one of the many points of future research.
References
[1]. D'haeseleer, P. (2006). What are DNA sequence motifs? Nature Biotech. 24, 423 - 425. doi:10.1038/nbt0406-423 http://www.nature.com.ezproxy.library.wisc.edu/nbt/journal/v24/n4/full/nbt0406-423.html
[2]. MEME. retrieved Apr. 15, 2014. http://nbcr-222.ucsd.edu/opal-jobs/appMEME_4.9.113970635652351481237017/meme.html#motifs
[3]. The MEME Suite: GOMO. retrieved Apr. 15, 2014. http://meme.nbcr.net/meme/gomo-intro.html
[4]. Fillman S.G. et. al. Markers of inflammation and stress distinguish subsets of individuals with schizophrenia and bipolar disorder. Transl Psychiatry. 2014 Feb 25; doi: 10.1038/tp.2014.8. http://www.ncbi.nlm.nih.gov/pubmed/?term=Fillman+markers+of+inflammation+and+stress+schizophrenia
[2]. MEME. retrieved Apr. 15, 2014. http://nbcr-222.ucsd.edu/opal-jobs/appMEME_4.9.113970635652351481237017/meme.html#motifs
[3]. The MEME Suite: GOMO. retrieved Apr. 15, 2014. http://meme.nbcr.net/meme/gomo-intro.html
[4]. Fillman S.G. et. al. Markers of inflammation and stress distinguish subsets of individuals with schizophrenia and bipolar disorder. Transl Psychiatry. 2014 Feb 25; doi: 10.1038/tp.2014.8. http://www.ncbi.nlm.nih.gov/pubmed/?term=Fillman+markers+of+inflammation+and+stress+schizophrenia