Allele-specific DNA demethylation editing leads to stable upregulation of allele-specific gene expression

Epigenome editing is an emerging technology that allows to rewrite epigenome states and reprogram gene expression. Here, we have developed allele-specific DNA demethylation editing at gene promoters containing an SNP by sgRNA/dCas9 mediated recuitment of TET1. Maximal DNA demethylation (up to 90%) was observed 6 days after transient transfection of the epigenome editors and it was almost stable for 15 days. After allele-specific targeting, DNA demethylation was up to 15-fold more efficient at the targeted allele. Our data show that locus-specific and allele-specific DNA demethylation can trigger the expression of previously silenced genes. Allele-specific DNA demethylation shifted allelic expression ratios about 4-fold. Allele-specific DNA demethylation could be used to correct aberrant imprinting in patients suffering from imprinting disorders and to study the roles of individual alleles of a gene in a given cellular context.