Systematic comparison of CRISPR-based transcriptional activators uncovers gene-regulatory features of enhancer–promoter interactions

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dc.citation.firstpage7842en_US
dc.citation.issueNumber14en_US
dc.citation.journalTitleNucleic Acids Researchen_US
dc.citation.lastpage7855en_US
dc.citation.volumeNumber50en_US
dc.contributor.authorWang, Kaiyuanen_US
dc.contributor.authorEscobar, Marioen_US
dc.contributor.authorLi, Jingen_US
dc.contributor.authorMahata, Barunen_US
dc.contributor.authorGoell, Jacoben_US
dc.contributor.authorShah, Spenceren_US
dc.contributor.authorCluck, Madeleineen_US
dc.contributor.authorHilton, Isaac Ben_US
dc.contributor.orgBioengineeringen_US
dc.contributor.orgBiosciencesen_US
dc.date.accessioned2022-09-08T14:40:03Zen_US
dc.date.available2022-09-08T14:40:03Zen_US
dc.date.issued2022en_US
dc.description.abstractNuclease-inactivated CRISPR/Cas-based (dCas-based) systems have emerged as powerful technologies to synthetically reshape the human epigenome and gene expression. Despite the increasing adoption of these platforms, their relative potencies and mechanistic differences are incompletely characterized, particularly at human enhancer–promoter pairs. Here, we systematically compared the most widely adopted dCas9-based transcriptional activators, as well as an activator consisting of dCas9 fused to the catalytic core of the human CBP protein, at human enhancer–promoter pairs. We find that these platforms display variable relative expression levels in different human cell types and that their transactivation efficacies vary based upon the effector domain, effector recruitment architecture, targeted locus and cell type. We also show that each dCas9-based activator can induce the production of enhancer RNAs (eRNAs) and that this eRNA induction is positively correlated with downstream mRNA expression from a cognate promoter. Additionally, we use dCas9-based activators to demonstrate that an intrinsic transcriptional and epigenetic reciprocity can exist between human enhancers and promoters and that enhancer-mediated tracking and engagement of a downstream promoter can be synthetically driven by targeting dCas9-based transcriptional activators to an enhancer. Collectively, our study provides new insights into the enhancer-mediated control of human gene expression and the use of dCas9-based activators.en_US
dc.identifier.citationWang, Kaiyuan, Escobar, Mario, Li, Jing, et al.. "Systematic comparison of CRISPR-based transcriptional activators uncovers gene-regulatory features of enhancer–promoter interactions." <i>Nucleic Acids Research,</i> 50, no. 14 (2022) Oxford University Press: 7842-7855. https://doi.org/10.1093/nar/gkac582.en_US
dc.identifier.digitalgkac582en_US
dc.identifier.doihttps://doi.org/10.1093/nar/gkac582en_US
dc.identifier.urihttps://hdl.handle.net/1911/113196en_US
dc.language.isoengen_US
dc.publisherOxford University Pressen_US
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleSystematic comparison of CRISPR-based transcriptional activators uncovers gene-regulatory features of enhancer–promoter interactionsen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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