Enhanced CRISPR-based DNA demethylation by Casilio-ME-mediated RNA-guided coupling of methylcytosine oxidation and DNA repair pathways

Aziz Taghbalout, Menghan Du, Nathaniel Jillette, Wojciech Rosikiewicz, Abhijit Rath, Christopher D. Heinen, Sheng Li and Albert W. Cheng ()
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Aziz Taghbalout: The Jackson Laboratory for Genomic Medicine
Menghan Du: The Jackson Laboratory for Genomic Medicine
Nathaniel Jillette: The Jackson Laboratory for Genomic Medicine
Wojciech Rosikiewicz: The Jackson Laboratory for Genomic Medicine
Abhijit Rath: University of Connecticut Health
Christopher D. Heinen: University of Connecticut Health
Sheng Li: The Jackson Laboratory for Genomic Medicine
Albert W. Cheng: The Jackson Laboratory for Genomic Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Here we develop a methylation editing toolbox, Casilio-ME, that enables not only RNA-guided methylcytosine editing by targeting TET1 to genomic sites, but also by co-delivering TET1 and protein factors that couple methylcytosine oxidation to DNA repair activities, and/or promote TET1 to achieve enhanced activation of methylation-silenced genes. Delivery of TET1 activity by Casilio-ME1 robustly alters the CpG methylation landscape of promoter regions and activates methylation-silenced genes. We augment Casilio-ME1 to simultaneously deliver the TET1-catalytic domain and GADD45A (Casilio-ME2) or NEIL2 (Casilio-ME3) to streamline removal of oxidized cytosine intermediates to enhance activation of targeted genes. Using two-in-one effectors or modular effectors, Casilio-ME2 and Casilio-ME3 remarkably boost gene activation and methylcytosine demethylation of targeted loci. We expand the toolbox to enable a stable and expression-inducible system for broader application of the Casilio-ME platforms. This work establishes a platform for editing DNA methylation to enable research investigations interrogating DNA methylomes.

Date: 2019
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DOI: 10.1038/s41467-019-12339-7

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