Differences in human and chimpanzee gene expression patterns define an evolving network of transcription factors in brain

Abstract

Humans differ from other primates by marked differences in cognitive abilities and a significantly larger brain. These differences correlate with metabolic changes, as evidenced by the relative up-regulation of energy-related genes and metabolites in human brain. While the mechanisms underlying these evolutionary changes have not been elucidated, altered activities of key transcription factors (TFs) could play a pivotal role. To assess this possibility, we analyzed microarray data from five tissues from humans and chimpanzees. We identified 90 TF genes with significantly different expression levels in human and chimpanzee brain among which the rapidly evolving KRAB-zinc finger genes are markedly over-represented. The differentially expressed TFs cluster within a robust regulatory network consisting of two distinct but interlinked modules, one strongly associated with energy metabolism functions, and the other with transcription, vesicular transport, and ubiquitination. Our results suggest that concerted changes in a relatively small number of interacting TFs may coordinate major gene expression differences in human and chimpanzee brain.

Fig. 1.

Percentage of differentially expressed genes among human and chimpanzee tissues. The proportion of all genes (white), all transcription factors (light gray), all KRAB-ZNF (KZNF) genes (gray), conserved KRAB-ZNF genes (dark gray), or primate-specific KRAB-ZNF genes (black) that are differentially expressed between species (t test, P < 0.01) is shown separately for each tissue. Asterisks mark values that represent significant enrichment. Numbers of genes per category are between 7 and 6,720.

Fig. 2.

Strategy to obtain TF-associated gene sets. Summary of the strategy used to identify positively and negatively associated gene sets for the network analysis. Details are described in the text.

Fig. 3.

Weighted topological overlap network between brain-changed transcription factors. Using as an input the correlations of the full set of TF-associated genes in human samples, the wTO network was calculated between the 79 ubiquitously expressed brain-changed transcription factors (∣ω_ij∣ > 0.3). TFs up-regulated in human brain compared with chimpanzee brain are shown in red, and down-regulated TFs are shown in green. Positive and negative links between TFs are shown in red and green, respectively. Numbers label the four TFs with the highest BC scores.

Fig. 4.

Difference in number of species-specific links among TFs in the human and chimpanzee wTO network. For each TF, the difference in the number of human- vs. chimpanzee-specific links is plotted. For definition of species-specific links, see the text. Genes with the largest numbers of human-specific links are positioned at top. The mean difference is 1.3 and 2 SDs are 10.3.

Fig. 5.

GO categories over-represented among genes associated with the TFs of each module. The program FUNC (25) was used to test for GO categories enriched among associated gene sets of TFs of each module. The sizes of the pie segments are proportional to the number of genes annotated in a given enriched (P < 0.05) GO category. The legend is sorted by size of the pie segments, going from the biggest to the smallest segment in Module 1 and then from the smallest to the biggest segment in Module 2.