Physiological Role and Mechanisms of Action for a Long Noncoding Haplotype Region

Hong Xue,Manoj K. Mishra,Yong Liu,Pengyuan Liu,Michael Grzybowski,Rajan Pandey,Kristie Usa, Mark A. Vanden Avond, Niharika Bala,Abdel A. Alli, Allen W. Cowley, Qiongzi Qiu,Andrew S. Greene,Sridhar Rao,Caitlin C. O'Meara,Aron M. Geurts,Mingyu Liang

Cell Reports（2025）

Department of Physiology

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Abstract

Direct targeting of noncoding genomic regions harboring common sequence variants associated with human traits through in vivo animal model studies and precise genome editing in human cells is essential for closing the critical gap between genetic discoveries and physiological understanding. However, such investigation has been impractical for many of these variants as they are in haplotypes containing multiple single-nucleotide polymorphisms (SNPs) spanning thousands of base pairs and have small effect sizes. We developed an integrated approach to address this challenge, combining an efficient two-step technique to precisely edit large haplotypes in human induced pluripotent stem cells and orthologous region deletion in phenotypically permissive animal models. As proof of principle, we applied this approach to examine a blood pressure-associated locus with a noncoding haplotype containing 11 SNPs spanning 17.4 kbp. We found a robust blood pressure effect of nearly 10 mmHg and identified the physiological and molecular mechanisms involved.

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Key words

noncoding,haplotype,single-nucleotide polymorphism,genome editing,induced pluripotent stem cells,animal model,blood pressure,salt,hypertension,chromatin interaction

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