Deciphering Species-Specific and Conserved Regulation of HumanUCP1Gene Expression: Insights from Predicted Homeodomain Family Transcription Factor Binding Sites

Abstract

While the potential of adipocyte thermogenesis in influencing metabolic diseases is well-recognized, its precise regulatory mechanisms remain elusive. To address this, we explore the complex network of transcription factors (TFs) governing the human UCP1 gene, a central player in thermogenesis, to shed light on regulatory processes driving human fat cell phenotypes. By employing computational analyses, we screen UCP1 ortholog and paralog promoters across humans, mice and rats to uncover conserved and species-specific regulatory elements. Leveraging transcriptomic data, chipSeq results and AdioNET phenotyping we delineate TFs potentially bind to the human UCP1 promoter. Significant sequence variation is revealed in the enhancer regions of UCP1s, characterised by the absence of large segments in the rodent genome, potentially influenced by the presence/absence of repetitive elements. Furthermore, our analyses identify species-specific regulatory hotspots mostly recognized by homeodomain family TFs providing the potential for the formation of enhanceosomes with nearby TFs. Exploring phylogenetically conserved regulatory elements reveals TFs exhibiting binding sites across species and UCP paralogs assigning again homeodomain family TFs among others, and bHLH TFs, respectively. These results potentially advance our understanding of thermogenic fat cell development and offer new targets for intervention in metabolic disorders.