Leveraging Cross- Species Transcription Factor Binding Site Patterns: From Diabetes Risk Loci to Disease Mechanisms

被引：92

作者：

Claussnitzer, Melina ^{[1
,2
,3
,4
,5
,6
]}

Dankel, Simon N. ^{[7
,8
,9
]}

Klocke, Bernward ^{[10
]}

Grallert, Harald ^{[3
,11
]}

Glunk, Viktoria ^{[1
,2
,3
,4
,5
]}

Berulava, Tea ^{[12
]}

Lee, Heekyoung ^{[1
,2
,3
,4
,5
]}

Oskolkov, Nikolay ^{[13
]}

Fadista, Joao ^{[13
]}

Ehlers, Kerstin ^{[1
,2
,3
,4
,5
]}

Wahl, Simone ^{[3
,11
]}

Hoffmann, Christoph ^{[2
,14
]}

Qian, Kun ^{[1
,2
,3
,4
,5
]}

Ronn, Tina ^{[13
]}

Riess, Helene ^{[15
,16
]}

Mueller-Nurasyid, Martina ^{[17
,18
,19
]}

Bretschneider, Nancy ^{[10
]}

Schroeder, Timm ^{[20
,21
]}

Skurk, Thomas ^{[1
,2
,32
]}

Horsthemke, Bernhard ^{[12
]}

Spieler, Derek ^{[22
,23
]}

Klingenspor, Martin ^{[2
,14
]}

Seifert, Martin ^{[10
]}

Kern, Michael J. ^{[24
]}

Mejhert, Niklas ^{[25
]}

Dahlman, Ingrid ^{[25
]}

Hansson, Ola ^{[13
]}

Hauck, Stefanie M. ^{[3
,26
]}

Blueher, Matthias ^{[27
]}

Arner, Peter ^{[25
]}

Groop, Leif ^{[13
]}

Illig, Thomas ^{[11
,28
]}

Suhre, Karsten ^{[29
,30
]}

Hsu, Yi-Hsiang ^{[6
,31
]}

Mellgren, Gunnar ^{[7
,8
,9
]}

Hauner, Hans ^{[1
,2
,3
,4
,5
,32
]}

Laumen, Helmut ^{[1
,2
,3
,4
,5
,33
]}

机构：

[1] Tech Univ Munich, Else Kroner Fresenius Ctr Nutr Med, Chair Nutr Med, D-85350 Freising Weihenstephan, Germany

[2] Tech Univ Munich, ZIEL Res Ctr Nutr & Food Sci, Nutr Med Unit, D-85350 Freising Weihenstephan, Germany

[3] German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany

[4] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Clin Cooperat Grp Nutrigenom & Type Diabet 2, D-85764 Neuherberg, Germany

[5] Tech Univ Munich, D-85350 Freising Weihenstephan, Germany

[6] Harvard Univ, Sch Med, Hebrew SeniorLife Inst Aging Res, Boston, MA 02131 USA

[7] Univ Bergen, Dept Clin Sci, N-5021 Bergen, Norway

[8] Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Diabet Res, N-5021 Bergen, Norway

[9] Haukeland Hosp, Hormone Lab, N-5021 Bergen, Norway

[10] Genomatix Software GmbH, D-80335 Munich, Germany

[11] Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany

[12] Univ Duisburg Essen, Univ Klinikum Essen, Inst Humangenet, D-45147 Essen, Germany

[13] Lund Univ, Dept Clin Sci, Diabet & Endocrinol Res Unit, S-20502 Malmo, Sweden

[14] Tech Univ Munich, Else Kroner Fresenius Ctr Nutr Med, Chair Mol Nutr Med, D-85350 Freising Weihenstephan, Germany

[15] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89081 Ulm, Germany

[16] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany

[17] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany

[18] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, D-81377 Munich, Germany

[19] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany

[20] German Res Ctr Environm Hlth GmbH, Helmholtz Ctr Munich, Res Unit Stem Cell Dynam, D-85764 Neuherberg, Germany

[21] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn D BSSE, CH-4058 Basel, Switzerland

[22] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany

[23] Tech Univ Munich, Klinikum Rechts Isar, Dept Neurol, D-81675 Munich, Germany

[24] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA

[25] Karolinska Univ Hosp Huddinge, Ctr Endocrinol & Metab, Karolinska Inst, Dept Med, SE-14186 Stockholm, Sweden

[26] Helmholtz Zentrum Munchen, Res Unit Prot Sci, D-85764 Neuherberg, Germany

[27] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany

[28] Hannover Med Sch, Hanover Unified Biobank, D-30625 Hannover, Germany

[29] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Bioinformat & Syst Biol, D-85764 Neuherberg, Germany

[30] Qatar Fdn, Weill Cornell Med Coll Qatar, Dept Physiol & Biophys, Doha, Qatar

[31] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA

[32] Tech Univ Munich, Klinikum Rechts Isar, Else Kroner Fresenius Ctr Nutr Med, D-81675 Munich, Germany

[33] Helmholtz Zentrum Munchen, Inst Expt Genet, D-85764 Neuherberg, Germany

来源：

CELL | 2014年 / 156卷 / 1-2期

基金：

瑞典研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; PHOSPHOENOLPYRUVATE CARBOXYKINASE; EPIGENOMIC ANALYSIS; ADIPOSE-TISSUE; LARGE-SCALE; PPAR-GAMMA; IN-VIVO; GENE; PPAR-GAMMA-2; VARIANT;

D O I：

10.1016/j.cell.2013.10.058

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：343 / 358

页数：16

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