Young transposable elements rewired gene regulatory networks in human and chimpanzee hippocampal intermediate progenitors

The hippocampus is associated with essential brain functions, such as learning and memory. Human hippocampal volume is significantly greater than expected compared with that of non-human apes, suggesting a recent expansion. Intermediate progenitors, which are able to undergo multiple rounds of proliferative division before a final neurogenic division, may have played a role in evolutionary hippocampal expansion. To investigate the evolution of gene regulatory networks underpinning hippocampal neurogenesis in apes, we leveraged the differentiation of human and chimpanzee induced pluripotent stem cells into TBR2 (or EOMES)-positive hippocampal intermediate progenitor cells (hpIPCs). We found that the gene networks active in hpIPCs are significantly different between humans and chimpanzees, with similar to 2500 genes being differentially expressed. We demonstrate that species-specific transposon-derived enhancers contribute to these transcriptomic differences. Young transposons, predominantly endogenous retroviruses and SINE-Vntr-Alus (SVAs), were co-opted as enhancers in a species -specific manner. Human-specific SVAs provided substrates for thousands of novel TBR2-binding sites, and CRISPR-mediated repression of these SVAs attenuated the expression of similar to 25% of the genes that are upregulated in human intermediate progenitors relative to the same cell population in the chimpanzee.

Automated summary

The hippocampus is involved in important brain functions, and it has recently undergone expansion in humans compared to non-human apes. The gene networks active in hippocampal intermediate progenitor cells are significantly different between humans and chimpanzees, with transposon-derived enhancers playing a role in these differences. Human-specific SVAs serve as substrates for novel TBR2-binding sites.