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Sc-RNA-seq for study: A human-specific enhancer fine-tunes radial glia potency and corticogenesis

ABSTRACT: Humans evolved an extraordinarily expanded and complex cerebral cortex, associated with developmental and gene regulatory modifications1-3. Human accelerated regions (HARs) are highly conserved DNA sequences with human-specific nucleotide substitutions. Although there are thousands of annotated HARs, their functional contribution to species-specific cortical development is largely unknown4,5. HARE5 is a HAR transcriptional enhancer of the WNT signaling receptor Frizzled8 (FZD8) active during brain development6. Here, using genome-edited mouse and primate models, we demonstrate that human (Hs) HARE5 fine-tunes cortical development and connectivity by controlling the proliferative and neurogenic capacity of neural progenitor cells (NPCs). Hs-HARE5 knock-in mice have significantly enlarged neocortices, which contain more excitatory neurons. By measuring neural dynamics in vivo we show these anatomical features result in increased functional independence between cortical regions. To understand the underlying developmental mechanisms, we assess progenitor fate using fixed and live imaging, lineage analysis, and single-cell RNA sequencing. We discover Hs-HARE5 modifies radial glial progenitor behavior, with increased self-renewal at early developmental stages followed by expanded neurogenic potential later. We use genome-edited human and chimpanzee (Pt) NPCs and cortical organoids to assess the relative enhancer activity and function of Hs-HARE5 and Pt-HARE5. Using these orthogonal strategies we show four human-specific variants in HARE5 drive increased enhancer activity which promotes progenitor proliferation. Finally, we show that Hs-HARE5 promotes progenitor proliferation by increasing canonical WNT signaling. These findings illustrate how small changes in regulatory DNA can directly impact critical signaling pathways to modulate brain development. Our study uncovers new functions for HARs as key regulatory elements crucial for the expansion and complexity of the human cerebral cortex.

ORGANISM(S): Mus musculus

PROVIDER: GSE288849 | GEO | 2025/03/06

REPOSITORIES: GEO

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Project description:Humans evolved an extraordinarily expanded and complex cerebral cortex, associated with developmental and gene regulatory modifications1-3. Human accelerated regions (HARs) are highly conserved DNA sequences with human-specific nucleotide substitutions. Although there are thousands of annotated HARs, their functional contribution to species-specific cortical development is largely unknown4,5. HARE5 is a HAR transcriptional enhancer of the WNT signaling receptor Frizzled8 (FZD8) active during brain development6. Here, using genome-edited mouse and primate models, we demonstrate that human (Hs) HARE5 fine-tunes cortical development and connectivity by controlling the proliferative and neurogenic capacity of neural progenitor cells (NPCs). Hs-HARE5 knock-in mice have significantly enlarged neocortices, which contain more excitatory neurons. By measuring neural dynamics in vivo we show these anatomical features result in increased functional independence between cortical regions. To understand the underlying developmental mechanisms, we assess progenitor fate using fixed and live imaging, lineage analysis, and single-cell RNA sequencing. We discover Hs-HARE5 modifies radial glial progenitor behavior, with increased self-renewal at early developmental stages followed by expanded neurogenic potential later. We use genome-edited human and chimpanzee (Pt) NPCs and cortical organoids to assess the relative enhancer activity and function of Hs-HARE5 and Pt-HARE5. Using these orthogonal strategies we show four human-specific variants in HARE5 drive increased enhancer activity which promotes progenitor proliferation. Finally, we show that Hs-HARE5 promotes progenitor proliferation by increasing canonical WNT signaling. These findings illustrate how small changes in regulatory DNA can directly impact critical signaling pathways to modulate brain development. Our study uncovers new functions for HARs as key regulatory elements crucial for the expansion and complexity of the human cerebral cortex.

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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Sc-RNA-seq for study: A human-specific enhancer fine-tunes radial glia potency and corticogenesis

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