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Modular cytosine base editing promotes epigenomic and genomic modifications


Weischedel, Julian; Higgins, Laurence; Rogers, Sally; Gramalla-Schmitz, Anna; Wyrzykowska, Paulina; Borgoni, Simone; MacCarthy, Thomas; Chahwan, Richard (2024). Modular cytosine base editing promotes epigenomic and genomic modifications. Nucleic Acids Research, 52(2):e8.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
08 Research Priority Programs > Translational Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Genetics
Language:English
Date:25 January 2024
Deposited On:31 Jan 2024 09:25
Last Modified:30 Jun 2024 01:38
Publisher:Oxford University Press
ISSN:0305-1048
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/nar/gkad1118
PubMed ID:37994786
Project Information:
  • : FunderFP7
  • : Grant ID241309
  • : Project TitleDEMOYS - Dense membranes for efficient oxygen and hydrogen separation
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  • : FunderTranslational Cancer Research
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  • : FunderSwiss Excellence Scholarship
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  • : FunderFunctional Genomics Center Zurich
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  • : FunderETH Zurich
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  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)