Molecular Signature Fetal Astrocyte Evolution in Primates

Astrocytes contribute to the establishment and regulation of the brain's higher-level functions. Evolutionary changes in astrocyte activity during development and adulthood likely help establish the unique cognitive capacities of the human brain. However, while the transcriptional differences between human and non-human primate (NHP) adult astrocytes are increasingly better defined, the molecular signature of fetal astrocyte evolution is unknown. We used human, chimpanzee, and macaque induced pluripotent stem cell-derived astrocytes (iAstrocytes) as a robust source of fetal astrocytes. Human iAstrocytes are bigger and more complex than NHP iAstrocytes. We found new loci and cellular pathways related to the interspecies differences in astrocyte size and complexity. Strikingly, genes that feature lower expression in human than in NHP iAstrocytes frequently relate to neurological disorders, including intellectual disability, opening new questions on the relationship between evolution and the higher-level mental capacities of our brain.Evolution is largely fuelled by changes in gene activity, which in turn arise as a corollary to genetic modification of distal DNA regulatory elements, including enhancers. Enhancers evolve fast. Yet, whether there are general and broadly applicable sequence changes that lead to functional activation of enhancers in evolution remains enigmatic. Our multilevel regulome analysis and machine learning revealed that functional activation of astrocytic enhancers coincides with a previously unappreciated, pervasive gain of binding sites of 'stripe' transcription factors, which are general transcriptional regulators. Altogether, we uncover genes and pathways linked to fetal astrocyte evolution and shed new light on a mechanism driving the acquisition of the regulatory potential of enhancers.