Sequence Independent Phylogenetic Footprinting Analysis Identifies Novel Transcription Regulation for Orexin Receptors

Abstract

The orexin receptors (OX1/2R) are G‐protein coupled receptors involved in the regulation of energy metabolism (Tsujino et al. 2009). Current evidence suggests that changes in expression of the OX1/2R are implicated in the development of obesity (Teske et al. 2006). However, there is limited information about the transcriptional regulation of these receptors. A sequence‐independent phylogenetic footprinting bioinformatic analysis of the OXR promoters from six species (human, rat, mouse, chimpanzee, dog and cow) identified several transcription factor binding sites (TFBS). Our preliminary results indicate the transcription factors (TFs) SP1, NFATc2, EGR1 and PPARγ are involved in the transcriptional regulation of OX1/2R. These TFs have been implicated in several rodent models of obesity, yet their specific role in the brain is undefined (Plagemann et al. 2009, van Beekum et al. 2009, T. C. Yang et al. 2006). This study is ongoing and we are currently analyzing TFBS co‐occurrences and OXR promoter's enhancer structures. Simultaneously, we have started working towards validation of the TFBS predictions in set of new immortalized rat hypothalamic cell lines, which either contain or do not contain both OXR. These findings will provide novel insight into the transcriptional regulation of the OX1/2R.Funding: The Department of Veterans Affairs and the National Institute of Health, NIDDK, DK078985‐02S2.