genome-wide location analysis reveals distinct transcriptional circuitry by paralogous regulators foxa1 and foxa2全基因组分析显示位置不同的转录电路paralogous监管机构foxa1 foxa2.pdfVIP

Genome-Wide Location Analysis Reveals Distinct Transcriptional Circuitry by Paralogous Regulators Foxa1 and Foxa2 1¤ 1 1 2 2 Irina M. Bochkis , Jonathan Schug , Diana Z. Ye , Svitlana Kurinna , Sabrina A. Stratton , 2 1 Michelle C. Barton , Klaus H. Kaestner * 1 Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America, 2 Center for Stem Cell and Developmental Biology, Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America Abstract Gene duplication is a powerful driver of evolution. Newly duplicated genes acquire new roles that are relevant to fitness, or they will be lost over time. A potential path to functional relevance is mutation of the coding sequence leading to the acquisition of novel biochemical properties, as analyzed here for the highly homologous paralogs Foxa1 and Foxa2 transcriptional regulators. We determine by genome-wide location analysis (ChIP-Seq) that, although Foxa1 and Foxa2 share a large fraction of binding sites in the liver, each protein also occupies distinct regulatory elements in vivo. Foxa1-only sites are enriched for p53 binding sites and are frequently found near genes important to cell cycle regulation, while Foxa2- restricted sites show only a limited match to the forkhead consensus and are found in genes involved in steroid and lipid metabolism. Thus, Foxa1 and Foxa2, while redundant during development, have evolved divergent roles in the adult liver, ensuring the maintenance of