Allele-specific quantitative proteomics unravels molecular mechanisms modulated by cis-regulatory PPARG locus variation.
Genome-wide association studies identified numerous disease risk loci. Delineating molecular mechanisms influenced by cis-regulatory variants is essential to understand gene regulation and ultimately disease pathophysiology. Combining bioinformatics and public domain chromatin information with quantitative proteomics supports prediction of cis-regulatory variants and enabled identification of allele-dependent binding of both, transcription factors and coregulators at the type 2 diabetes associated PPARG locus. We found rs7647481A nonrisk allele binding of Yin Yang 1 (YY1), confirmed by allele-specific chromatin immunoprecipitation in primary adipocytes. Quantitative proteomics also found the coregulator RING1 and YY1 binding protein (RYBP) whose mRNA levels correlate with improved insulin sensitivity in primary adipose cells carrying the rs7647481A nonrisk allele. Our findings support a concept with diverse cis-regulatory variants contributing to disease pathophysiology at one locus. Proteome-wide identification of both, transcription factors and coregulators, can profoundly improve understanding of mechanisms underlying genetic associations.
Else Kroener-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, Technische Universität München, 85354 Freising-Weihenstephan, Germany.|ZIEL - Institute for Food & Health, Technische Universität München, 85354 Freising-Weihenstephan, Germany.|Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München and Technische Universität München, 85354 Freising-Weihenstephan, Germany.|German Center for Diabetes Research (DZD), Germany.
Heekyoung
H
Lee
Else Kroener-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, Technische Universität München, 85354 Freising-Weihenstephan, Germany.|ZIEL - Institute for Food & Health, Technische Universität München, 85354 Freising-Weihenstephan, Germany.|Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München and Technische Universität München, 85354 Freising-Weihenstephan, Germany.|German Center for Diabetes Research (DZD), Germany.|Research Unit Protein Science, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Kun
K
Qian
German Center for Diabetes Research (DZD), Germany.|Research Unit Protein Science, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Christine
C
von Toerne
ZIEL - Institute for Food & Health, Technische Universität München, 85354 Freising-Weihenstephan, Germany.|Else Kroener-Fresenius-Center for Nutritional Medicine, Paediatric Nutritional Medicine, Technische Universität München, 85354 Freising-Weihenstephan, Germany.
Lena
L
Hoerburger
Else Kroener-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, Technische Universität München, 85354 Freising-Weihenstephan, Germany.|ZIEL - Institute for Food & Health, Technische Universität München, 85354 Freising-Weihenstephan, Germany.|Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München and Technische Universität München, 85354 Freising-Weihenstephan, Germany.|German Center for Diabetes Research (DZD), Germany.|Hebrew SeniorLife Institute for Aging Research, Harvard Medical School, Boston, MA 02131, USA.
Melina
M
Claussnitzer
ZIEL - Institute for Food & Health, Technische Universität München, 85354 Freising-Weihenstephan, Germany.|Else Kroener-Fresenius-Center for Nutritional Medicine, Chair of Molecular Nutritional Medicine, Technische Universität München, 85354 Freising-Weihenstephan, Germany.
Christoph
C
Hoffmann
Else Kroener-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, Technische Universität München, 85354 Freising-Weihenstephan, Germany.|ZIEL - Institute for Food & Health, Technische Universität München, 85354 Freising-Weihenstephan, Germany.|Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München and Technische Universität München, 85354 Freising-Weihenstephan, Germany.|German Center for Diabetes Research (DZD), Germany.
Viktoria
V
Glunk
German Center for Diabetes Research (DZD), Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
Simone
S
Wahl
German Center for Diabetes Research (DZD), Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
Michaela
M
Breier
Research Unit Protein Science, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Franziska
F
Eck
Research Unit Protein Science, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Leili
L
Jafari
German Center for Diabetes Research (DZD), Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
Sophie
S
Molnos
Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München and Technische Universität München, 85354 Freising-Weihenstephan, Germany.|German Center for Diabetes Research (DZD), Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
Harald
H
Grallert
Department of Medicine, Huddinge, Karolinska Institutet, SE-141 86 Stockholm, Sweden.
Ingrid
I
Dahlman
Department of Medicine, Huddinge, Karolinska Institutet, SE-141 86 Stockholm, Sweden.
Peter
P
Arner
Klinik für Hals-Nasen-Ohrenheilkunde, Universitätsklinik Ulm, 89075 Ulm, Germany.
Cornelia
C
Brunner
Else Kroener-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, Technische Universität München, 85354 Freising-Weihenstephan, Germany.|ZIEL - Institute for Food & Health, Technische Universität München, 85354 Freising-Weihenstephan, Germany.|Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München and Technische Universität München, 85354 Freising-Weihenstephan, Germany.|German Center for Diabetes Research (DZD), Germany.|Else Kroener-Fresenius-Center for Nutritional Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
Hans
H
Hauner
German Center for Diabetes Research (DZD), Germany.|Research Unit Protein Science, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Stefanie M
SM
Hauck
Else Kroener-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, Technische Universität München, 85354 Freising-Weihenstephan, Germany.|ZIEL - Institute for Food & Health, Technische Universität München, 85354 Freising-Weihenstephan, Germany.|Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München and Technische Universität München, 85354 Freising-Weihenstephan, Germany.|German Center for Diabetes Research (DZD), Germany.|Research Unit Protein Science, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Else Kroener-Fresenius-Center for Nutritional Medicine, Paediatric Nutritional Medicine, Technische Universität München, 85354 Freising-Weihenstephan, Germany.|Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Helmut
H
Laumen
D000273:Adipose Tissue / Q000378:metabolism; D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D056426:Genetic Loci; D014644:Genetic Variation; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D051379:Mice; D047495:PPAR gamma / Q000235:genetics*; D040901:Proteomics; D051381:Rats; D050436:Regulatory Elements, Transcriptional; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D050986:YY1 Transcription Factor / Q000378:metabolism
D004268:DNA-Binding Proteins; D047495:PPAR gamma; D014157:Transcription Factors; D050986:YY1 Transcription Factor