Neither genome size nor gene number is indicative of organism complexity. Complex regulation of genes within a genome likely contributes to organism complexity. Coordinate regulation of genes through shared cis regulatory elements is one such mechanism. Peptide tyrosine tyrosine (PYY) and N-acetylglutamate synthase (NAGS) are divergently transcribed and thus share a 5 flanking region, raising the possibility these genes are coordinately regulated through common cis regulatory elements. These genes are separated by less than 1000 base pairs and may be regulated by a bidirectional promoter. The purpose of this project is to investigate the molecular and physiologic relationship between PYY and NAGS. To locate the promoter region, the transcriptional start sites (TSSs) for these genes were identified in multiple tissues. Results of these experiments demonstrate the major TSSs for PYY and NAGS are separated by greater than 1000 base pairs indicating they are not under control of a bidirectional promoter by the strict definition. However, they may share cis regulatory elements in the intergenic region. Expression of PYY and NAGS was determined in a panel of human tissues, revealing distinct expression patterns for these genes. Importantly, PYY and NAGS are similarly expressed in the ileum, indicating that if the genes are coordinately regulated it is in a tissue-specific manner. To better understand the physiologic connection between these two genes, plasma PYY levels were measured in patients with diminished capacity for nitrogen processing. Plasma PYY levels were increased in these patients and therefore may contribute to some of the clinical symptoms in this group. Finally, results from in vivo studies in mouse point toward possible coordinate expression of PYY and NAGS in response to different feeding conditions. Taken together the data are consistent with the coordinate regulation of PYY and NAGS, and lead to a model in which these genes are coordinately regulated as a means to prevent overconsumption of dietary protein. This mechanism may explain, in part, why protein is more satiating than other macronutrients and may also help elucidate the mechanisms of nitrogen balance.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-12022010-150524 |
| Date | 07 December 2010 |
| Creators | Mitchell, Sabrina L. |
| Contributors | Dana C. Crawford, Douglas P. Mortlock, Alyssa H. Hasty, P. Anthony Weil, Deborah G. Murdock, Marshall L. Summar |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-12022010-150524/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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