Targeted DNA methylation editing in vivo [mouse brain]

Establishing the causation of these associations, despite the rapid development of epigenome editing tools, remains challenging, particularly in vivo. In this study, we developed and characterized three Cre-dependent CRISPR-based mouse lines that enable locus-specific DNA methylation deposition by either constitutive or inducible dCas9-DNMT3A expression.

We demonstrate robust locus-specific DNA methylation deposition of MHC class II (H2-Ab1) and interleukin 6 (Il6) genes in bone marrow-derived myeloid cells ex vivo. Moreover, neuron-specific targeting results in decreased cannabinoid receptor 1 (Cnr1) expression in striatal neurons in vivo. Notably, we demonstrate that the causal effect of DNA methylation on gene expression is locus-dependent, reinforcing the necessity of such editing tools for detailed understanding of the role of DNA methylation and for addressing the causality of disease-associated CpGs.