The hippocampus plays a major role in learning and memory and is also associated with the evolution of human-specific traits. Hippocampal volume in humans is significantly greater than that in non-human apes, but the mechanisms driving this increase are unclear. Now, Marco Trizzino and colleagues reveal that transposable elements (TEs) contribute to species-specific differences in hippocampal intermediate progenitor cells (hpIPCs) - cells that undergo multiple rounds of proliferative divisions and are thus hypothesized to influence hippocampal expansion. The authors first develop induced pluripotent stem cell-derived models of human and chimpanzee hpIPCs. By comparing these cells, they show that key neurodevelopmental genes are differentially expressed between human and chimpanzee hpIPCs. Using ATAC-seq, they also uncover human-specific chromatin accessibility patterns in hpIPCs. Specifically, young TEs, such as endogenous retroviruses and SINE-Vntr-Alus (SVAs), are enriched in accessible regions in human hpIPCs. Moreover, human-specific SVAs are enriched for binding motifs for the transcription factor TBR2 (EOMES), which regulates hippocampal neurogenesis. Finally, the researchers demonstrate that CRISPR-mediated SVA repression in retinoic acid-treated NCCIT cells, which also model hpIPCs, causes widespread changes in genes that exhibit human-specific expression patterns. Based on these findings, the authors propose that young TEs were co-opted into enhancers that rewired gene regulatory networks in the human hippocampus and potentially led to its expansion.
