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

Melina Claussnitzer; 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 Horsthemke; DIAGRAM+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

doi:10.1016/j.cell.2013.10.058

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 journal › Article › peer-review

96 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 language	English
Pages (from-to)	343-358
Number of pages	16
Journal	Cell
Volume	156
Issue number	1-2
DOIs	https://doi.org/10.1016/j.cell.2013.10.058
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2013.10.058

http://www.scopus.com/record/display.url?eid=2-s2.0-84892689100&origin=resultslist&sort=plf-f&src=s&st1=Leveraging+cross-species+transcription+factor+binding+site+patterns&sid=680E8B21FB435435777B6BD65B400E8C.WXhD7YyTQ6A7Pvk9AlA%3a880&sot=b&sdt=b&sl=82&s=TITLE-ABS-KEY%28Leveraging+cross-species+transcription+factor+binding+site+patterns%29&relpos=0&relpos=0&citeCnt=9&searchTerm=TITLE-ABS-KEY%28Leveraging+cross-species+transcription+factor+binding+site+patterns%29

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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

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

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.",

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",

author = "Melina Claussnitzer and Dankel, {Simon N.} and Bernward Klocke and Harald Grallert and Viktoria Glunk and Tea Berulava and Heekyoung Lee and Nikolay Oskolkov and Joao Fadista and Kerstin Ehlers and Simone Wahl and Christoph Hoffmann and Kun Qian and Tina R{\"o}nn and Helene Riess and Martina M{\"u}ller-Nurasyid and Nancy Bretschneider and Timm Schroeder and Thomas Skurk and Bernhard Horsthemke and DIAGRAM+Consortium and Derek Spieler and Martin Klingenspor and Martin Seifert and Kern, {Michael J.} and Niklas Mejhert and Ingrid Dahlman and Ola Hansson and Hauck, {Stefanie M.} and Matthias Bl{\"u}her and Peter Arner and Leif Groop and Thomas Illig and Karsten Suhre and Yi-Hsiang Hsu and Gunnar Mellgren and Hans Hauner and Helmut Laumen and Palmer, {Colin Neil Alexander}",

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Claussnitzer, 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, DIAGRAM+Consortium, 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 & Laumen, H 2014, 'Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms', Cell, vol. 156, no. 1-2, pp. 343-358. https://doi.org/10.1016/j.cell.2013.10.058

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 - DIAGRAM+Consortium

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

AU - Palmer, Colin Neil Alexander

PY - 2014/1/16

Y1 - 2014/1/16

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.

KW - Animals

KW - Cell Line

KW - Cells, Cultured

KW - Conserved Sequence

KW - Diabetes Mellitus, Type 2

KW - Gene Expression Regulation

KW - Genome-Wide Association Study

KW - Homeodomain Proteins

KW - Humans

KW - Insulin Resistance

KW - PPAR gamma

KW - Polymorphism, Single Nucleotide

KW - Regulatory Sequences, Nucleic Acid

KW - Transcription Factors

U2 - 10.1016/j.cell.2013.10.058

DO - 10.1016/j.cell.2013.10.058

M3 - Article

C2 - 24439387

SN - 0092-8674

VL - 156

SP - 343

EP - 358

JO - Cell

JF - Cell

IS - 1-2

ER -

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

Abstract

Keywords

UN SDGs

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