Massively parallel disruption of enhancers active in human neural stem cells.

Autor:	Geller E; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA., Noble MA; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA., Morales M; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA., Gockley J; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA., Emera D; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA., Uebbing S; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA., Cotney JL; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA., Noonan JP; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Wu Tsai Institute, Yale University, New Haven, CT 06510, USA. Electronic address: james.noonan@yale.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Feb 27; Vol. 43 (2), pp. 113693. Date of Electronic Publication: 2024 Jan 23.
DOI:	10.1016/j.celrep.2024.113693
Abstrakt:	Changes in gene regulation have been linked to the expansion of the human cerebral cortex and to neurodevelopmental disorders, potentially by altering neural progenitor proliferation. However, the effects of genetic variation within regulatory elements on neural progenitors remain obscure. We use sgRNA-Cas9 screens in human neural stem cells (hNSCs) to disrupt 10,674 genes and 26,385 conserved regions in 2,227 enhancers active in the developing human cortex and determine effects on proliferation. Genes with proliferation phenotypes are associated with neurodevelopmental disorders and show biased expression in specific fetal human brain neural progenitor populations. Although enhancer disruptions overall have weaker effects than gene disruptions, we identify enhancer disruptions that severely alter hNSC self-renewal. Disruptions in human accelerated regions, implicated in human brain evolution, also alter proliferation. Integrating proliferation phenotypes with chromatin interactions reveals regulatory relationships between enhancers and their target genes contributing to neurogenesis and potentially to human cortical evolution. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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