**2.3 Transcriptional regulation of mammalian OTC gene**

The human *OTC* gene is 70 kb long and has 10 exons which contain a 1062 bp long coding sequence [65]. Transcription of the human *OTC* gene initiates at multiple transcription start sites (TSS) [66], while transcription of the mouse and rat *Otc* genes initiate at a single transcription start site located 136 and 98 bp upstream of the translation initiation codon [67, 68]. Within the rat *Otc* promoter, four regions, A–D, bind transcription factors that regulate expression of the *Otc* gene [31]. Region A is a negative regulator of *Otc* transcription [31], and transcription factors that bind to this region have not been identified. Regions B and C bind transcriptional activator HNF4, and transcriptional repressor chicken ovalbumin upstream promoter—transcription factor (COUP-TF) [30, 31]. Region D is located downstream of the transcription start site and its role in expression of the *Otc* gene remains to be elucidated [31].

The rat *Otc* promoter is sufficient for expression of transgenes in the liver and intestine of transgenic mice [69, 70]. An enhancer located approximately 11 kb upstream of the first exon of the rat *Otc* gene is responsible for a high level of expression of the *Otc* gene in the liver [31]. This −11 kb enhancer has four transcription factor-binding sites, designated I–IV [31]; sites I and II bind C/EBPβ, while transcription factor HNF4 binds to sites I and IV in the rat *Otc* enhancer to activate expression of the *Otc* gene [32, 37, 38]. Since comparative genomics studies revealed that the distance between regions that correspond to the −11 kb rat *Otc* enhancer and OTC promoter vary in mammalian genomes, this region was renamed as the liver-specific enhancer (LSE) [71].
