Cross species comparison of C/EBPα and PPARγ profiles in mouse and human adipocytes reveals interdependent retention of binding sites

Background: The transcription factors peroxisome proliferator activated receptor gamma (PPAR gamma) and CCAAT/enhancer binding protein alpha (C/EBP alpha) are key transcriptional regulators of adipocyte differentiation and function. We and others have previously shown that binding sites of these two transcription factors show a high degree of overlap and are associated with the majority of genes upregulated during differentiation of murine 3T3 L1 adipocytes. Results: Here we have mapped all binding sites of C/EBP alpha and PPAR gamma in human SGBS adipocytes and compared these with the genome-wide profiles from mouse adipocytes to systematically investigate what biological features correlate with retention of sites in orthologous regions between mouse and human. Despite a limited interspecies retention of binding sites, several biological features make sites more likely to be retained. First, co-binding of PPAR gamma and C/EBP alpha in mouse is the most powerful predictor of retention of the corresponding binding sites in human. Second, vicinity to genes highly upregulated during adipogenesis significantly increases retention. Third, the presence of C/EBP alpha consensus sites correlate with retention of both factors, indicating that C/EBP alpha facilitates recruitment of PPAR gamma. Fourth, retention correlates with overall sequence conservation within the binding regions independent of C/EBP alpha and PPAR gamma sequence patterns, indicating that other transcription factors work cooperatively with these two key transcription factors. Conclusions: This study provides a comprehensive and systematic analysis of what biological features impact on retention of binding sites between human and mouse. Specifically, we show that the binding of C/EBP alpha and PPAR gamma in adipocytes have evolved in a highly interdependent manner, indicating a significant cooperativity between these two transcription factors.