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Comparative characterization of human accelerated regions in neurons [PIPseq]

ABSTRACT: Human accelerated regions (HARs) are conserved genomic loci that have experienced rapid nucleotide substitutions following the divergence from chimpanzees. HARs are enriched in candidate regulatory regions near neurodevelopmental genes, suggesting their roles in gene regulation. However, their target genes and functional contributions to human brain development remain largely uncharacterized. Here, we elucidate the cis-regulatory functions of HARs in human and chimpanzee induced pluripotent stem cell (iPSC)-induced excitatory neurons. Using genomic and chromatin looping information, we prioritized 20 HARs and their chimpanzee orthologs for functional characterization via single-cell CRISPRi, and demonstrated their species-specific gene regulatory functions. Our findings reveal diverse functional outcomes of HAR-mediated cis-regulation in human neurons, including attenuated NPAS3 expression by altering the binding affinities of multiple transcription factors in HAR202 and maintaining iPSC pluripotency and neuronal differentiation capacities through the upregulation of PUM2 by 2xHAR.319. Finally, we use prime editing to demonstrate differential enhancer activity caused by several HAR26;2xHAR.178 variants. In particular, we link one variant in HAR26;2xHAR.178 to elevated SOCS2 expression and increased neurite outgrowth in human neurons. Thus, our study sheds new light on the endogenous gene regulatory functions of HARs and their potential contribution to human brain evolution.

ORGANISM(S): Homo sapiens Pan troglodytes

PROVIDER: GSE269798 | GEO | 2024/11/12

REPOSITORIES: GEO

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Project description:Human Accelerated Regions (HARs) are highly conserved across species but exhibit a significant excess of human-specific sequence changes, suggesting they may have gained novel functions in human evolution. HARs include gene regulatory elements with human-specific activity and have been implicated in the evolution of the human brain. However, our understanding of how HARs contributed to uniquely human features of the brain is hindered by a lack of insight into the genes and pathways that HARs regulate. It is unknown whether HARs acted by altering the expression of gene targets conserved between HARs and their chimpanzee orthologs or by gaining new gene targets in human, a mechanism termed enhancer hijacking. We generated a high-resolution map of chromatin interactions for 1,590 HARs and their orthologs in human and chimpanzee neural stem cells (NSCs) to comprehensively identify gene targets in both species. HARs and their chimpanzee orthologs targeted a conserved set of 2,963 genes enriched for neurodevelopmental processes including neurogenesis and synaptic transmission. Changes in HAR enhancer activity were correlated with changes in conserved gene target expression. Conserved targets were enriched among genes differentially expressed between human and chimpanzee NSCs or between human and non-human primate developing and adult brain. Species-specific HAR gene targets did not converge on known biological functions and were not significantly enriched among differentially expressed genes, suggesting that most HARs did not alter gene expression via enhancer hijacking. HAR gene targets, including differentially expressed targets, also showed cell type-specific expression patterns in the developing human brain, notably in outer radial glia, which are hypothesized to contribute to human cortical expansion. Our findings support that HARs influenced human brain evolution by altering the expression of a conserved set of gene targets and provide the means to functionally link HARs with novel human brain features.

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Comparative characterization of human accelerated regions in neurons [PIPseq]

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