a combination of genomic approaches reveals the role of foxo1a in regulating an oxidative stress response pathway结合基因组方法揭示foxo1a的作用在调节氧化应激反应途径.pdfVIP

A Combination of Genomic Approaches Reveals the Role of FOXO1a in Regulating an Oxidative Stress Response Pathway 1 1 1 2 1 Paola de Candia *, Ran Blekhman , Adrien E. Chabot , Alicia Oshlack , Yoav Gilad * 1 Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America, 2 Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Abstract Background: While many of the phenotypic differences between human and chimpanzee may result from changes in gene regulation, only a handful of functionally important regulatory differences are currently known. As a first step towards identifying transcriptional pathways that have been remodeled in the human lineage, we focused on a transcription factor, FOXO1a, which we had previously found to be up-regulated in the human liver compared to that of three other primate species. We concentrated on this gene because of its known role in the regulation of metabolism and in longevity. Methodology: Using a combination of expression profiling following siRNA knockdown and chromatin immunoprecip- itation in a human liver cell line, we identified eight novel direct transcriptional targets of FOXO1a. This set includes the gene for thioredoxin-interacting protein (TXNIP), the expression of which is directly repressed by FOXO1a. The thioredoxin- interacting protein is known to inhibit the reducing activity of thioredoxin (TRX), thereby hindering the cellular response to oxidative stress and affecting life span. Conclusions: Our results provide an explanation for the repeated observations that differences in the regulation of FOXO transcription factors affect longevity. Moreover, we found that TXNIP is down-regulated in human compar