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Title page for ETD etd-12022010-150524


Type of Document Dissertation
Author Mitchell, Sabrina L.
URN etd-12022010-150524
Title Investigation into the molecular and physiologic relationship between peptide tyrosine tyrosine and N-acetylglutamate synthase
Degree PhD
Department Human Genetics
Advisory Committee
Advisor Name Title
Douglas P. Mortlock Committee Chair
Alyssa H. Hasty Committee Member
Dana C. Crawford Committee Member
Deborah G. Murdock Committee Member
Marshall L. Summar Committee Member
P. Anthony Weil Committee Member
Keywords
  • urea cycle disorders
  • nitrogen
  • urea cycle
  • protein
Date of Defense 2010-09-30
Availability unrestricted
Abstract
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.
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