Expression profiling by high throughput sequencing Genome binding/occupancy profiling by high throughput sequencing
Summary
Brain development is exceptionally delayed in humans compared to nonhuman primates (NHPs), a finding often termed neoteny. Signatures of neoteny, including a protracted proliferation of apical and basal progenitors as well as a delay in physiological activity of mature neurons, have been revealed in part through the use of induced pluripotent stem cell (iPSC) modeling of primate neurogenesis. IPSC modeling is particularly useful when examining the molecular drivers of a cellular phenotype such as gene transcription. It has long been proposed that phenotypic differences between closely related species may be driven, in part, by divergent transcriptional regulation rather than novel protein-coding sequence, however, how these regulatory mechanisms play a role in the protracted maturation process in human neurons remains largely unknown. Here we show that the transcription factor GATA3 directly regulates the rate of physiological maturity in human neurons. We modeled neurogenesis across 5 primate species consisting of 4 genera and 2 families and assessed the differences in transcriptional dynamics. We discovered that GATA3, a pioneer transcription factor, exhibited a unique up-regulation during human neurogenesis and was highly correlated with species-specific transcription. Strikingly, we also found that down-regulating GATA3 generated a gain-of-function, speeding up the rate of physiological maturity in human neurons. These findings indicate that the rate of physiological maturity in human neurons can be directly controlled by modulating a single, conserved transcription factor, providing evidence for the divergence of gene regulation as a major contributor to human neoteny.
Overall design
RNA- and ChIP-sequencing from human, chimpanzee, bonobo, gorilla, and rhesus macaque neurons throughout pan-neuronal differentiation, sampled at 2 week intervals over an 8 week period.
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