Comparative characterization of human accelerated regions in neurons

Xiekui Cui, Han Yang, Charles Cai, Cooper Beaman, Xiaoyu Yang, Hongjiang Liu, Xingjie Ren, Zachary Amador, Ian R. Jones, Kathleen C. Keough, Meng Zhang, Tyler Fair, Armen Abnousi, Shreya Mishra, Zhen Ye, Ming Hu, Alex A. Pollen, Katherine S. Pollard and Yin Shen ()
Additional contact information
Xiekui Cui: University of California, San Francisco
Han Yang: University of California, San Francisco
Charles Cai: University of California, San Francisco
Cooper Beaman: University of California, San Francisco
Xiaoyu Yang: University of California, San Francisco
Hongjiang Liu: University of California, San Francisco
Xingjie Ren: University of California, San Francisco
Zachary Amador: University of California, San Francisco
Ian R. Jones: University of California, San Francisco
Kathleen C. Keough: University of California, San Francisco
Meng Zhang: University of California, San Francisco
Tyler Fair: Univeristy of California, San Francisco
Armen Abnousi: Cleveland Clinic Foundation
Shreya Mishra: Cleveland Clinic Foundation
Zhen Ye: University of California, San Francisco
Ming Hu: Cleveland Clinic Foundation
Alex A. Pollen: Univeristy of California, San Francisco
Katherine S. Pollard: University of California, San Francisco
Yin Shen: University of California, San Francisco

Nature, 2025, vol. 640, issue 8060, 991-999

Abstract: Abstract Human accelerated regions (HARs) are conserved genomic loci that have experienced rapid nucleotide substitutions following the divergence from chimpanzees1,2. HARs are enriched in candidate regulatory regions near neurodevelopmental genes, suggesting their roles in gene regulation3. 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 (iPS) cell-induced excitatory neurons. Using genomic4 and chromatin looping information, we prioritized 20 HARs and their chimpanzee orthologues for functional characterization via single-cell CRISPR interference, 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 iPS cell pluripotency and neuronal differentiation capacities through the upregulation of PUM2 by 2xHAR.319. Finally, we used 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.

Date: 2025
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DOI: 10.1038/s41586-025-08622-x

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