Functional targets of the monogenic diabetes transcription factors HNF-1alpha and HNF-4alpha 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)-1alpha and -4alpha 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-1alpha- and HNF-4alpha-deficient diabetes. However, the significance of studies that assess binding without considering regulatory function is poorly understood.


METHODS
We compared previously reported mouse and human HNF-1alpha and HNF-4alpha 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-1alpha and -4alpha binding, yet observed incomplete detection of binding in the different datasets, causing an underestimation of binding conservation. Second, only a minor fraction of HNF-1alpha- and HNF-4alpha-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-1alpha and -4alpha are largely conserved between mice and humans.
Boj
Sylvia F
SF
Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Servitja
Joan Marc
JM
Martin
David
D
Rios
Martin
M
Talianidis
Iannis
I
Guigo
Roderic
R
Ferrer
Jorge
J
D000818:Animals; D017124:Conserved Sequence; D015536:Down-Regulation; D019143:Evolution, Molecular; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D051379:Mice; D013045:Species Specificity; D014158:Transcription, Genetic
C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse