Homeodomain transcription factors in adipocyte thermogenesis: insights into the species-specific and conserved regulatory elements of human UCP1

Abstract

AbstractAdipocyte thermogenesis is a promising target for treating metabolic disorders, but its regulatory mechanisms remain unclear. This study investigates transcription factors (TFs) and regulatory elements that may control the humanUCP1gene, which is essential for thermogenesis and the formation of the adipocyte phenotype. Using the Eukaryota Promoter Database, we performed computational analyses of theUCP1, UCP2andUCP3promoter sequences in humans, mice and rats to identify conserved and species-specific elements. We also used transcriptome data from human neck-derived adipocytes and databases (Contra v3, ChiPBase, TFlink, AdipoNet, ISMARA, etc.) to narrow potential regulatory TFs. Our results show that mouse and ratUCP1enhancers lack large segments, primarily due to the insertion of repetitive elements that are already lost in some clades. We identified key TFs such as PPARA, PPARG, THR, RARE, RXR, JUN, TFAP2 and SREBF1 as general regulators ofUCPs.Additionally, human-specificUCP1regulatory hotspots (e.g. 5’-TCTAATTAGA-3’) recognised by homeodomain TFs (e.g. EN1, PAX4, HOXA5 and PRRX2) and NFIL3 were detected. Phylogenetically conserved regulatory elements suggest common TFs in humanUCP1paralogues (MAX, MYCN, MNT, HES1) and cross-species (POU6F1). These results improve our understanding of thermogenic adipocyte development and provide new therapeutic targets for metabolic diseases.Graphical Abstract