Epi-Allele elicits compensatory expression of the non-targeted allele and prevents haploinsufficiency in dominant genetic diseases PMID: 42692018

Antimicrobial Resistance: From Resistance Mechanisms to Emerging Research Strategies

2026-11-05

Epi-Allele elicits compensatory expression of the non-targeted allele and prevents haploinsufficiency in dominant genetic diseases

Cell Stem Cell. 2026 Oct 1;33(10):1676-1694.e11. doi: 10.1016/j.stem.2026.08.004.

Zhengmin Wang ¹ , Chengzhi Han ¹ , Yiming Huang ² , Yuyuan Fu ¹ , Kaijie Hu ² , Zheyong Huang ³ , Weiying Meng ⁴ , Qiyao Chen ³ , Leilei Wu ⁵ , Qiaozi Wang ³ , Jinyan Zhang ³ , Hao Luo ⁵ , Yifan Wang ⁵ , Lulu Zuo ² , Yingqi Li ⁵ , Yiwen Tan ³ , Qin Zhou ² , Shaoshuai Mao ⁵ , Wenbo Peng ⁵ , Juan Meng ² , Maoxiang Chen ³ , Zhiyang Tian ² , Shuwei Chen ³ , Zihan Hu ³ , Lu Zhao ² , Yihan Shen ² , Shanshan Chen ² , Zhixin Shen ² , Lijuan Mo ² , Jinfeng Gao ³ , Qiyu Li ³ , Shiteng Cai ³ , Jianhuang Xue ⁶ , Yanan Song ⁷ , Yidi Sun ⁸ , Junbo Ge ⁹ , Changyang Zhou ¹⁰

Affiliations

1. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200031, China; Institute of Neuroscience, State Key Laboratory of Genetic Evolution & Animal Models, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200031, China.
2. Institute of Neuroscience, State Key Laboratory of Genetic Evolution & Animal Models, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
3. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200031, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200031, China.
4. Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital affiliated to Tongji University, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
5. Epigenic Therapeutics, Inc., Shanghai 201315, China.
6. Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital affiliated to Tongji University, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. Electronic address: [email protected].
7. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200031, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200031, China. Electronic address: [email protected].
8. Institute of Neuroscience, State Key Laboratory of Genetic Evolution & Animal Models, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Key Laboratory of Precision Gene Editing and Clinical Translation, Shanghai 200031, China. Electronic address: [email protected].
9. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200031, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200031, China. Electronic address: [email protected].
10. Institute of Neuroscience, State Key Laboratory of Genetic Evolution & Animal Models, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Key Laboratory of Precision Gene Editing and Clinical Translation, Shanghai 200031, China. Electronic address: [email protected].

Abstract

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.

Keywords

DNA methylation; allele-specific therapy; chromatin remodeling; compensatory allele expression; dominant genetic diseases; epigenetic editing; haploinsufficiency; hypertrophic cardiomyopathy; transcription factors.