Lee Heekyoung, Qian Kun, von Toerne Christine, Hoerburger Lena, Claussnitzer Melina, Hoffmann Christoph, Glunk Viktoria, Wahl Simone, Breier Michaela, Eck Franziska, Jafari Leili, Molnos Sophie, Grallert Harald, Dahlman Ingrid, Arner Peter, Brunner Cornelia, Hauner Hans, Hauck Stefanie M, Laumen Helmut
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.
Nucleic Acids Res. 2017 Apr 7;45(6):3266-3279. doi: 10.1093/nar/gkx105.
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.
全基因组关联研究确定了众多疾病风险位点。阐明受顺式调控变异影响的分子机制对于理解基因调控以及最终理解疾病病理生理学至关重要。将生物信息学和公共领域的染色质信息与定量蛋白质组学相结合，有助于预测顺式调控变异，并能够识别转录因子和共调节因子在2型糖尿病相关PPARG位点上的等位基因依赖性结合。我们发现了阴阳1（YY1）与rs7647481A非风险等位基因的结合，这在原代脂肪细胞中通过等位基因特异性染色质免疫沉淀得到了证实。定量蛋白质组学还发现了共调节因子RING1和YY1结合蛋白（RYBP），其mRNA水平与携带rs7647481A非风险等位基因的原代脂肪细胞中改善的胰岛素敏感性相关。我们的研究结果支持了这样一个概念，即多种顺式调控变异在一个位点上促成疾病病理生理学。对转录因子和共调节因子进行全蛋白质组鉴定，可以深刻提高对遗传关联潜在机制的理解。
