A combination of genomic approaches reveals the role of FOXO1a in regulating an oxidative stress response pathway.
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.


METHODS
Using a combination of expression profiling following siRNA knockdown and chromatin immunoprecipitation 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 compared to chimpanzee, consistent with the up-regulation of its direct repressor FOXO1a in humans, and with differences in longevity between the two species.
de Candia
Paola
P
Department of Human Genetics, University of Chicago, Chicago, Illinois, USA. pdecandi@bsd.uchicago.edu
Blekhman
Ran
R
Chabot
Adrien E
AE
Oshlack
Alicia
A
Gilad
Yoav
Y
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D005786:Gene Expression Regulation; D023281:Genomics / Q000379:methods*; D006801:Humans; D008136:Longevity; D018384:Oxidative Stress; D002679:Pan troglodytes
D002352:Carrier Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C486715:TXNIP protein, human