Allele-specific quantitative proteomics unravels molecular mechanisms modulated by cis-regulatory PPARG locus variation

作者：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^*

来源：Nucleic Acids Research, 2017, 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 non-risk 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.

• 出版日期2017-4-7