Zhengmin Wang, Chengzhi Han, Yiming Huang, Yuyuan Fu, Kaijie Hu, Zheyong Huang, Weiying Meng, Qiyao Chen, Leilei Wu, Qiaozi Wang, Jinyan Zhang, Hao Luo, Yifan Wang, Lulu Zuo, Yingqi Li, Yiwen Tan, Qin Zhou, Shaoshuai Mao, Wenbo Peng, Juan Meng, Maoxiang Chen, Zhiyang Tian, Shuwei Chen, Zihan Hu, Lu Zhao, Yihan Shen, Shanshan Chen, Zhixin Shen, Lijuan Mo, Jinfeng Gao, Qiyu Li, Shiteng Cai, Jianhuang Xue, Yanan Song, Yidi Sun, Junbo Ge, Changyang Zhou
Epigenetic regulation may underlie asymmetric allelic expression of many genes during development and disease pathogenesis. Allele-specific epigenetic modification could provide an efficient therapy for dominant genetic diseases due to heterozygous mutations. We developed an allele-specific epigenetic editing method ("Epi-Allele") for silencing pathogenic alleles and found surprisingly elevated expression of the non-targeted alleles, leaving total gene expression unchanged. Genome-wide screening revealed that such compensated allelic expression represents a common phenomenon, suggesting that the Epi-Allele approach could avoid the haploinsufficiency induced by current allele-specific silencing therapies. This notion was validated by allele-specific epigenetic remodeling of Myh6 and MYH7 genes in ameliorating cardiac phenotypes in a hypertrophic cardiomyopathy (HCM) mouse model and HCM patient iPSC-derived cardiomyocytes, respectively. Thus, Epi-Allele offers an allele-specific haploinsufficiency-free therapeutic approach for treating dominant genetic diseases.