Massively parallel characterization of CRISPR activator efficacy in human induced pluripotent stem cells and neurons
文献类型： 外文期刊
作者： Wu, Qianxin 1 ; Wu, Junjing 1 ; Karim, Kaiser 2 ; Chen, Xi 1 ; Wang, Tengyao 5 ; Iwama, Sho 1 ; Carobbio, Stefania 1 ; Keen, Peter 1 ; Vidal-Puig, Antonio 1 ; Kotter, Mark R. 2 ; Bassett, Andrew 1 ;
作者机构： 1.Wellcome Sanger Inst, Cambridge CB10 1SA, England
2.Univ Cambridge, Dept Clin Neurosci, Cambridge CB20 QQ, England
3.Hubei Acad Agr Sci, Inst Anim Sci & Vet Med, Wuhan 430064, Peoples R China
4.Southern Univ Sci & Technol, 1088 Xueyuan Ave, Shenzhen 518055, Guangdong, Peoples R China
5.London Sch Econ & Polit Sci, Dept Stat, London WC2B 4RR, England
6.Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Metab Res Labs,Addenbrookes Treatment Ctr, Cambridge, England
7.Ctr Invest Principe Felipe, Valencia 46012, Spain
期刊名称：MOLECULAR CELL （ 影响因子：16.0； 五年影响因子：18.4 ）
ISSN： 1097-2765
年卷期： 2023 年 83 卷 7 期
页码：
收录情况： SCI
摘要： CRISPR activation (CRISPRa) is an important tool to perturb transcription, but its effectiveness varies be-tween target genes. We employ human pluripotent stem cells with thousands of randomly integrated bar-coded reporters to assess epigenetic features that influence CRISPRa efficacy. Basal expression levels are influenced by genomic context and dramatically change during differentiation to neurons. Gene activa-tion by dCas9-VPR is successful in most genomic contexts, including developmentally repressed regions, and activation level is anti-correlated with basal gene expression, whereas dCas9-p300 is ineffective in stem cells. Certain chromatin states, such as bivalent chromatin, are particularly sensitive to dCas9-VPR, whereas constitutive heterochromatin is less responsive. We validate these rules at endogenous genes and show that activation of certain genes elicits a change in the stem cell transcriptome, sometimes showing features of differentiated cells. Our data provide rules to predict CRISPRa outcome and highlight its utility to screen for factors driving stem cell differentiation.
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