Molecular signature of primate astrocytes reveals pathways and regulatory changes contributing to the human brain evolution

Abstract

Astrocytes contribute to the development and regulation of the higher-level functions of the brain, the critical targets of evolution. However, the molecular signature of foetal astrocyte evolution in primates is unknown. Here, to address this question, we use human, chimpanzee, and macaque induced pluripotent stem cell-derived foetal astrocytes (iAstrocytes). Human iAstrocytes are bigger and more complex than the non-human primate iAstrocytes. We find loci related to the regulation of cell size with increased expression in the human lineage. Likewise, we uncover that genes and mechanisms implicated in long-range intercellular signalling are activated in the human iAstrocytes. Strikingly, loci downregulated in the human lineage frequently relate to intellectual disability raising new questions on the trade-offs associated with the evolution of the human mind. Using our system, through a multilevel regulome analysis and machine learning, we uncover that functional activation of enhancers coincides with a previously unappreciated, pervasive gain of binding sites of stripe transcription factors. In summary, we shed new light on a mechanism driving the acquisition of the regulatory potential of enhancers.