Allele-specific epigenetic editing for silencing target gene pathogenic allele while elevating normal allele in autosomal dominant diseases. Mus musculus strain:57BL/6jR403Q/wt/wild-type DBA/2 | breed:57BL/6jR403Q/wt strain with wild-type DBA/2

Epigenetic treatment of autosomal dominant diseases requires precise targeting of pathogenic allele. We developed an allele-specific epigenetic editing method, termed Epi-Allele, which could reduce the expression of pathogenic allele while increase that of normal allele, leading to normal level of targeted gene expression. In a hypertrophic cardiomyopathy (HCM) model mice with gain-of-function Myh6 mutation, Epi-Allele achieved allele-specific epigenetic reshaping of Myh6 expression and prevented HCM cardiac phenotypes. In HCM patient iPSC-derived cardiomyocytes carrying MYH7 mutation, Epi-Allele also reshaped the expression of pathogenic vs. normal allele expression without affecting the total MYH7 expression. Finally, we showed that Epi-Allele reshaping of allele expression results from redistribution of transcription factors between mutated and normal alleles. Thus, Epi-Allele provides a potential allele-specific therapeutic approach for treating autosomal dominant diseases.