Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms

Melina Claussnitzer (Lead / Corresponding author), Simon N. Dankel, Bernward Klocke, Harald Grallert, Viktoria Glunk, Tea Berulava, Heekyoung Lee, Nikolay Oskolkov, Joao Fadista, Kerstin Ehlers, Simone Wahl, Christoph Hoffmann, Kun Qian, Tina Rönn, Helene Riess, Martina Müller-Nurasyid, Nancy Bretschneider, Timm Schroeder, Thomas Skurk, Bernhard HorsthemkeDIAGRAM+Consortium, Derek Spieler, Martin Klingenspor, Martin Seifert, Michael J. Kern, Niklas Mejhert, Ingrid Dahlman, Ola Hansson, Stefanie M. Hauck, Matthias Blüher, Peter Arner, Leif Groop, Thomas Illig, Karsten Suhre, Yi-Hsiang Hsu, Gunnar Mellgren, Hans Hauner, Helmut Laumen

    Research output: Contribution to journalArticle

    73 Citations (Scopus)

    Abstract

    Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.

    Original languageEnglish
    Pages (from-to)343-358
    Number of pages16
    JournalCell
    Volume156
    Issue number1-2
    DOIs
    Publication statusPublished - 16 Jan 2014

    Keywords

    • Animals
    • Cell Line
    • Cells, Cultured
    • Conserved Sequence
    • Diabetes Mellitus, Type 2
    • Gene Expression Regulation
    • Genome-Wide Association Study
    • Homeodomain Proteins
    • Humans
    • Insulin Resistance
    • PPAR gamma
    • Polymorphism, Single Nucleotide
    • Regulatory Sequences, Nucleic Acid
    • Transcription Factors

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  • Cite this

    Claussnitzer, M., Dankel, S. N., Klocke, B., Grallert, H., Glunk, V., Berulava, T., Lee, H., Oskolkov, N., Fadista, J., Ehlers, K., Wahl, S., Hoffmann, C., Qian, K., Rönn, T., Riess, H., Müller-Nurasyid, M., Bretschneider, N., Schroeder, T., Skurk, T., ... Laumen, H. (2014). Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms. Cell, 156(1-2), 343-358. https://doi.org/10.1016/j.cell.2013.10.058