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

TitleLeveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms.
Publication TypeJournal Article
Year of Publication2014
AuthorsClaussnitzer M, Dankel SN, 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, Horsthemke B, Spieler D, Klingenspor M, Seifert M, Kern MJ, Mejhert N, Dahlman I, Hansson O, Hauck SM, Blüher M, Arner P, Groop L, Illig T, Suhre K, Hsu Y-H, Mellgren G, Hauner H
Secondary AuthorsLaumen H
Corporate AuthorsDIAGRAM+Consortium
Date Published2014 Jan 16
KeywordsAnimals, Cell Line, Cells, Cultured, Conserved Sequence, Diabetes Mellitus, Type 2, Gene Expression Regulation, Genome-Wide Association Study, Homeodomain Proteins, Humans, Insulin Resistance, Polymorphism, Single Nucleotide, PPAR gamma, Regulatory Sequences, Nucleic Acid, Transcription Factors

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.

Alternate JournalCell
PubMed ID24439387
Grant ListMC_UU_12015/4 / / Medical Research Council / United Kingdom
MC_UU_12015/1 / / Medical Research Council / United Kingdom
MC_U106179471 / / Medical Research Council / United Kingdom
090532 / / Wellcome Trust / United Kingdom
MC_U106179474 / / Medical Research Council / United Kingdom