Modular cytosine base editing promotes epigenomic and genomic modifications

Abstract Prokaryotic and eukaryotic adaptive immunity differ considerably. Yet, their fundamental mechanisms of gene editing via Cas9 and activation-induced deaminase (AID), respectively, can be conveniently complimentary. Cas9 is an RNA targeted dual nuclease expressed in several bacterial species....

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Bibliographic Details
Published inNucleic acids research Vol. 52; no. 2; p. e8
Main Authors Weischedel, Julian, Higgins, Laurence, Rogers, Sally, Gramalla-Schmitz, Anna, Wyrzykowska, Paulina, Borgoni, Simone, MacCarthy, Thomas, Chahwan, Richard
Format Journal Article
LanguageEnglish
Published England Oxford University Press 25.01.2024
Subjects
CRISPR-Associated Protein 9 - metabolism
CRISPR-Cas Systems
Cytosine - chemistry
Cytosine Deaminase - genetics
Epigenomics - methods
Gene Editing - methods
Methods
RNA - genetics
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Summary:Abstract Prokaryotic and eukaryotic adaptive immunity differ considerably. Yet, their fundamental mechanisms of gene editing via Cas9 and activation-induced deaminase (AID), respectively, can be conveniently complimentary. Cas9 is an RNA targeted dual nuclease expressed in several bacterial species. AID is a cytosine deaminase expressed in germinal centre B cells to mediate genomic antibody diversification. AID can also mediate epigenomic reprogramming via active DNA demethylation. It is known that sequence motifs, nucleic acid structures, and associated co-factors affect AID activity. But despite repeated attempts, deciphering AID’s intrinsic catalytic activities and harnessing its targeted recruitment to DNA is still intractable. Even recent cytosine base editors are unable to fully recapitulate AID’s genomic and epigenomic editing properties. Here, we describe the first instance of a modular AID-based editor that recapitulates the full spectrum of genomic and epigenomic editing activity. Our ‘Swiss army knife’ toolbox will help better understand AID biology per se as well as improve targeted genomic and epigenomic editing. Graphical Abstract Graphical Abstract
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The first two authors should be regarded as Joint First Authors.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkad1118