TIGP (BIO)—Regulatory divergence between humans and chimpanzees

Abstract

In 1975, regulatory change was proposed to underlie the conspicuous phenotypic differences between humans and chimpanzees. This hypothesis remains unproven, although substantial supporting evidence has accumulated in the last two decades. Our study aimed to identify human-specific transcription factor (TF) target genes by predicting TF binding sites in gene promoters, which are the regions from the transcription start site (TSS) to 1000 bp upstream (-1000 bp). We divided a promoter into proximal (from TSS to -500 bp) and distal (from -500 bp to -1000 bp). We predicted 551 human-specific TF target genes. We focused on the 320 human-specific proximal TF target genes and found that 108 (34%) of them, a surprisingly high proportion, showed differential expression between human and gorilla developing cerebral organoids. Nine of these genes have neurobiological functions. Many genes were down regulated in the early time points of organoid development, they might contribute to the delayed transition from neuroepithelial (NE) cells to radial glia (RG) in forebrain development in humans compared to nonhuman apes. Also, we found 84 TFs that have predicted TFBSs on the proximal promoters of the target genes. In particular, ZEB2, which is a key regulator of the delayed cell type (NE-to-RG) transition that underlies human-specific forebrain expansion, showed lower expression in human than in gorilla developing cerebral organoids at all seven time points studied. Another very interesting finding is that NLGN1 (neuroligin-1) is not only down regulated in the early stage of human cerebral brain development but also in the posterior cingulate cortex. NLGN1 is a key protein in the neurexins and neuroligins integrated pathway, which controls synaptic signaling. Thus, we have found many human-specific TF target genes that might be involved in brain development. In conclusion, our study has provided good evidence for the importance of regulatory divergence in the evolution of human-specific traits, especially those involved in neurological function.

 

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