TY - JOUR
T1 - Leveraging cross-species transcription factor binding site patterns
T2 - From diabetes risk loci to disease mechanisms
AU - Claussnitzer, Melina
AU - Dankel, Simon N.
AU - Klocke, Bernward
AU - Grallert, Harald
AU - Glunk, Viktoria
AU - Berulava, Tea
AU - Lee, Heekyoung
AU - Oskolkov, Nikolay
AU - Fadista, Joao
AU - Ehlers, Kerstin
AU - Wahl, Simone
AU - Hoffmann, Christoph
AU - Qian, Kun
AU - Rönn, Tina
AU - Riess, Helene
AU - Müller-Nurasyid, Martina
AU - Bretschneider, Nancy
AU - Schroeder, Timm
AU - Skurk, Thomas
AU - Horsthemke, Bernhard
AU - Spieler, Derek
AU - Klingenspor, Martin
AU - Seifert, Martin
AU - Kern, Michael J.
AU - Mejhert, Niklas
AU - Dahlman, Ingrid
AU - Hansson, Ola
AU - Hauck, Stefanie M.
AU - Blüher, Matthias
AU - Arner, Peter
AU - Groop, Leif
AU - Illig, Thomas
AU - Suhre, Karsten
AU - Hsu, Yi Hsiang
AU - Mellgren, Gunnar
AU - Hauner, Hans
AU - Laumen, Helmut
N1 - Funding Information:
This work was funded by the Else Kröner-Fresenius Foundation, Bad Homburg v.d.H, Germany; the grant Virtual Institute “Molecular basis of glucose regulation and type 2 diabetes” received from the Helmholtz Zentrum München, München-Neuherberg, Germany; the grant Clinical Cooperation Group “Nutrigenomics and type 2 diabetes” received from the Helmholtz Zentrum München, München-Neuherberg, Germany, and the Technische Universität München; the Helmholtz Graduate School for Environmental Health, HELENA; a grant from the German Federal Ministry of Education and Research to the German Centre for Diabetes Research (DZD e.V.); the Competence Network Obesity (German Obesity Biomaterial Bank; FKZ 01GI1128), and the University Duisburg-Essen (01KU1216E); the KG Jebsen Center for Diabetes Research, University of Bergen, Norway and the Western Norway Regional Health Authority, Norway; by grants from the Swedish Research Council, including strategic research area grant EXODIAB (2009-1039), Linnaeus grant (349-2006-237), Collaborative Grant (2011-3315), and Project Grant (521-2010-3490) and by an ERC Advanced Researcher Grant GENETARGET-T2D (GA 269045); and by “Biomedical Research Program” funds at Weill Cornell Medical College in Qatar, a program funded by the Qatar Foundation. We thank Karl-Fredrik Eriksson and Targ Elgzyri for providing human fat biopsy material and Charlotte Ling for supporting generation of microarray data (Lund University). We are grateful to Andrea Califano (Columbia University, New York, NY) for critical review and constructive scientific comments on the manuscript. We further thank Bernd Baumann, Vidar M. Steen, and Jørn V. Sagen for expert advice, and Elisabeth Hofmair, Manuela Hubersberger, Margit Solsvik, Linn Jeanette Waagbø, Tone Nygaard Flølo, Jan-Inge Bjune, Zina Fandalyuk, Vivian Veum, and Christine Haugen for excellent technical assistance. We thank Ralf Kühn (Helmholtz Zentrum München, München-Neuherberg) for providing CRISPR/Cas vectors. We thank Christine Stansberg, Rita Holdhus, and Kjell Petersen at the Norwegian Microarray Consortium (NMC) (Bergen node, Norway), Douglas P. Kiel and David Karasik (Hebrew SeniorLife Institute for Aging Research, Harvard Medical School, Boston, MA), and Michael Molla (Joslin Diabetes Center, Harvard Medical School, Boston, MA) for expert assistance. We thank surgeon Hans Jørgen Nielsen and colleagues (Voss Hospital, Norway), surgeons Barbara Auras Jaatun, Inge Glambæk, and colleagues (Haraldsplass Deaconess Hospital, Bergen), surgeon Christian Busch (Klinikk Bergen, Nesttun), and all the patients for providing human adipose tissue. We thank Reiner Schroeer and Dorothy Dankel for critical reading of the manuscript. The authors have filed a patent related to this work.
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84892689100&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2013.10.058
DO - 10.1016/j.cell.2013.10.058
M3 - Article
C2 - 24439387
AN - SCOPUS:84892689100
SN - 0092-8674
VL - 156
SP - 343
EP - 358
JO - Cell
JF - Cell
IS - 1-2
ER -