Re-expressing Epigenetically Silenced Genes by Inducing DNA Demethylation Through Targeting of Ten-Eleven Translocation 2 to Any Given Genomic Locus.

Abstract

Epigenetic editing is a novel methodology to modify the epigenetic landscape of any genomic location. As such, the approach might reprogram expression profiles, without altering the DNA sequence. Epigenetic alterations, including promoter hypermethylation, are associated with an increasing number of human diseases. To exploit this situation, epigenetic editing rises as a new alternative to specifically demethylate abnormally hypermethylated regions. Here, we describe a methodology to actively demethylate the hypermethylated ICAM-1 promoter. Reducing DNA methylation in our target region increased the expression of the ICAM-1 gene. As the ICAM-1 gene in our cell lines was highly methylated (up to 80%), this approach proves a robust manner to reduce methylation for hypermethylated regions. Epigenetic editing therefore not only provides an approach to address mechanisms of gene expression regulation, but also adds to the therapeutic toolbox as current inhibitors of epigenetic enzymes are limited by genome-wide effects.