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Claussnitzer, M. ; Dankel, S.N.* ; Klocke, B.* ; Grallert, H. ; Glunk, V. ; Berulava, T.* ; Lee, H.K. ; 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.* ; DIAGRAM Consortium (Gieger, C. ; Huth, C. ; Klopp, N. ; Meitinger, T. ; Petersen, A.-K. ; Thorand, B. ; Wichmann, H.-E.) ; Spieler, D. ; Klingenspor, M. ; Seifert, M.* ; Kern, M.J.* ; Mehjert, N.* ; Dahlman, I.* ; Hansson, O.* ; Hauck, S.M. ; Blüher, M.* ; Arner, P.* ; Groop, L.* ; Illig, T. ; Suhre, K. ; Hsu, Y.H.* ; Mellgren, G.* ; Hauner, H. ; Laumen, H.

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

Cell 156, 343-358 (2014)
Verlagsversion Volltext DOI PMC
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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Review
Schlagwörter Genome-wide Association; Adipose-tissue; Phosphoenolpyruvate Carboxykinase; Insulin Sensitivity; Susceptibility Loci; Epigenomic Analysis; Large-scale; Ppar-gamma; In-vivo; Gene
Sprache englisch
Veröffentlichungsjahr 2014
HGF-Berichtsjahr 2014
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Zeitschrift Cell
Quellenangaben Band: 156, Heft: 1-2, Seiten: 343-358 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Cambridge, Mass.
Begutachtungsstatus Peer reviewed
Institut(e) CCG Nutrigenomics and Type 2 Diabetes (KKG-KDN)
Institute of Epidemiology (EPI)
Institute of Genetic Epidemiology (IGE)
Institute of Stem Cell Research (ISF)
Institute of Human Genetics (IHG)
CF Metabolomics & Proteomics (CF-MPC)
Institute of Bioinformatics and Systems Biology (IBIS)
Institute of Experimental Genetics (IEG)
POF Topic(s) 30502 - Diabetes: Pathophysiology, Prevention and Therapy
30202 - Environmental Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30204 - Cell Programming and Repair
30203 - Molecular Targets and Therapies
30505 - New Technologies for Biomedical Discoveries
90000 - German Center for Diabetes Research
30503 - Chronic Diseases of the Lung and Allergies
Forschungsfeld(er) Genetics and Epidemiology
Stem Cell and Neuroscience
Enabling and Novel Technologies
PSP-Element(e) G-521600-002
G-504091-002
G-504000-002
G-504100-001
G-500800-001
G-500700-001
G-505700-001
G-503700-001
G-501900-401
G-503900-001
G-501900-068
G-501900-066
PubMed ID 24439387
DOI 10.1016/j.cell.2013.10.058
WOS ID WOS:000329912200032
Scopus ID 84892689100
Erfassungsdatum 2014-01-20
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