Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-019-12339-7
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Funding
- Jackson Laboratory internal grants
- National Human Genome Research Institute [1R01HG009900]
- National Cancer Institute [P30CA034196]
- Leukemia Research Foundation New Investigator Grant
- Jackson Laboratory Director's Innovation fund [19000-17-31]
- Jackson Laboratory Cancer Center New Investigator Award
- National Cancer Institute of the National Institutes of Health [P30CA034196]
- National Institutes of Health [CA115783]
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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.
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