Abstract
BackgroundWhile 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.MethodologyUsing 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.ConclusionsOur 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.
Highlights
In addition to substitutions at the protein level, changes in gene regulation are likely to underlie many phenotypes of interest, including human-specific adaptations and diseases [1,2,3,4,5,6,7,8]
Our results provide an explanation for the repeated observations that differences in the regulation of FOXO transcription factors affect longevity
In order to identify human-specific changes in regulatory pathways, we focused on a transcription factor, the Forkhead box O1A transcription factor (FOXO1a), which we had previously found to be significantly up-regulated in human livers compared to that of three non-human primates [12]
Summary
In addition to substitutions at the protein level, changes in gene regulation are likely to underlie many phenotypes of interest, including human-specific adaptations and diseases [1,2,3,4,5,6,7,8]. In order to identify human-specific changes in regulatory pathways, we focused on a transcription factor, the Forkhead box O1A transcription factor (FOXO1a), which we had previously found to be significantly up-regulated in human livers compared to that of three non-human primates [12] We concentrated on this gene because of its pivotal role in the regulation of metabolism and in longevity (reviewed by [13]), a phenotype that differs markedly between humans and other primates [14]. 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
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