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

  1. Sylvia F. Boj1,
  2. Joan Marc Servitja1,
  3. David Martin2,
  4. Martin Rios3,
  5. Iannis Talianidis4,
  6. Roderic Guigo2 and
  7. Jorge Ferrer1
  1. 1Genomic Programming of Beta-cells Laboratory, Institut d′Investigacions Biomèdiques August Pi i Sunyer, and Endocrinology, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain;
  2. 2Center for Genomic Regulation, Barcelona, Spain;
  3. 3Department of Statistics, University of Barcelona School of Biology, Barcelona, Spain; and
  4. 4Biomedical Sciences Research Center Alexander Fleming, Athens, Greece.
  1. Corresponding author: Jorge Ferrer, jferrer{at}clinic.ub.es.
  1. S.F.B. and J.M.S. contributed equally to this work.

Abstract

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)-1α and -4α 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-1α– and HNF-4α–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-1α and HNF-4α 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-1α and -4α binding, yet observed incomplete detection of binding in the different datasets, causing an underestimation of binding conservation. Second, only a minor fraction of HNF-1α– and HNF-4α–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-1α and -4α are largely conserved between mice and humans.

Footnotes

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    • Received June 18, 2008.
    • Accepted January 20, 2009.
  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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  1. Diabetes vol. 58 no. 5 1245-1253
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