Functional Targets of the Monogenic Diabetes Transcription Factors HNF-1α and HNF-4α Are Highly Conserved Between Mice and Humans

OBJECTIVE-The evolutionary conservation of transcriptional mechanisms has been widely exploited to understand human biology and disease. Recent findings, however, unexpectedly showed that the transcriptional regulators hepatocyte nuclear factor (HNF)-1 alpha and -4 alpha rarely bind to the same genes in mice and humans, leading to the proposal that tissue-specific transcriptional regulation has undergone extensive divergence in the two species. Such observations have major implications for the use of mouse models to understand HNF-1 alpha- and HNF-4 alpha-deficient diabetes. However, the significance of studies that assess binding without, considering regulatory function is poorly understood. RESEARCH DESIGN AND METHODS-We compared previously reported mouse and human HNF-1 alpha and HNF-4 alpha binding studies with independent binding experiments. We also integrated binding studies with mouse and human loss-of-function gene expression datasets. RESULTS-First, we confirmed the existence of species-specific HNF-1 alpha and -4 alpha binding, yet observed incomplete detection of binding in the different datasets, causing an underestimation of binding conservation. Second, only a minor fraction of HNF-1 alpha- and HNF-4 alpha-bound genes were downregulated in the absence of these regulators. This subset, of functional targets did not show evidence for evolutionary divergence of binding or binding sequence motifs. Finally, we observed differences between conserved and species-specific binding properties. For example, conserved binding was more frequently located near transcriptional start sites and was more likely to involve multiple binding events in the same gene. CONCLUSIONS-Despite evolutionary changes in binding, essential direct transcriptional functions of HNF-1 alpha and -4 alpha are largely conserved between mice and humans. Diabetes 58: 1245-1253,2009