Rescue of imprinted genes by epigenome editing in human cellular models of Prader-Willi syndrome

Akisa Nemoto, Kent Imaizumi, Fuyuki Miya, Yuka Hiroi, Mamiko Yamada, Hirosato Ideno, Shinji Saitoh, Kenjiro Kosaki, Hironobu Okuno () and Hideyuki Okano ()
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Akisa Nemoto: Keio University School of Medicine
Kent Imaizumi: Keio University School of Medicine
Fuyuki Miya: Keio University School of Medicine
Yuka Hiroi: Tokyo Medical University
Mamiko Yamada: Keio University School of Medicine
Hirosato Ideno: Keio University School of Medicine
Shinji Saitoh: Nagoya City University Graduate School of Medical Sciences
Kenjiro Kosaki: Keio University School of Medicine
Hironobu Okuno: Keio University School of Medicine
Hideyuki Okano: Keio University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Prader-Willi syndrome (PWS) is a genomic imprinting disorder caused by the loss of function of the paternal chromosome 15q11-13, resulting in a spectrum of symptoms associated with hypothalamic dysfunction. PWS patients lack the expression of paternally expressed genes (PEGs) in the 15q11-13 locus but possess an epigenetically silenced set of these genes in the maternal allele. Thus, activation of these silenced genes can serve as a therapeutic target for PWS. Here, we leverage CRISPR-based epigenome editing system to modulate the DNA methylation status of the PWS imprinting control region (PWS-ICR) in induced pluripotent stem cells (iPSCs) derived from PWS patients. Successful demethylation in the PWS-ICR restores the PEG expression from the maternal allele and reorganizes the methylation patterns in other PWS-associated imprinted regions beyond the PWS-ICR. Remarkably, these corrected epigenomic patterns and PEG expression are maintained following the differentiation of these cells into hypothalamic organoids. Finally, the single-cell transcriptomic analysis of epigenome-edited organoids demonstrates a partial restoration of the transcriptomic dysregulation observed in PWS. This study highlights the utility of epigenome editing technology as a therapeutic approach in addressing PWS and potentially other imprinting disorders.

Date: 2025
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DOI: 10.1038/s41467-025-64932-8

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