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Nat. Commun., Published: 03 July 2025;16,6125(2025) | https://doi.org/10.1038/s41467-025-61156-8
Mechanism of EHMT2-mediated genomic imprinting associated with Prader-Willi syndrome
Sung Eun Wang1,2, Yubao Cheng1, Jaechul Lim3,4, Mi-Ae Jang5, Emily N. Forrest1, Yuna Kim6, Meaghan Donahue1, Sungsin Jo7, Sheng-Nan Qiao1, Dong Eun Lee2, Jun Young Hong2, Yan Xiong8, Jian Jin8, Siyuan Wang1,9 & Yong-hui Jiang1,10,11,12
1Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA.
2Department of Systems Biology, Yonsei University, Seoul, South Korea.
3Department of Immunobiology, Yale School of Medicine, Yale University, New Haven, CT, USA.
4College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, South Korea.
5Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
6Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
7Department of Biology, Soonchunhyang University, Asan, South Korea.
8Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9Department of Cell Biology, Yale School of Medicine, Yale University, New Haven, CT, USA.
10Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.
11Department of Pediatrics, Yale School of Medicine, Yale University, New Haven, CT, USA.
12Department of Ob/Gyn and Reproductive Science, Yale School of Medicine, Yale University, New Haven, CT 06520, USA.
Corresponding author
Correspondence to Yong-hui Jiang.
1Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA.
2Department of Systems Biology, Yonsei University, Seoul, South Korea.
3Department of Immunobiology, Yale School of Medicine, Yale University, New Haven, CT, USA.
4College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, South Korea.
5Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
6Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
7Department of Biology, Soonchunhyang University, Asan, South Korea.
8Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9Department of Cell Biology, Yale School of Medicine, Yale University, New Haven, CT, USA.
10Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.
11Department of Pediatrics, Yale School of Medicine, Yale University, New Haven, CT, USA.
12Department of Ob/Gyn and Reproductive Science, Yale School of Medicine, Yale University, New Haven, CT 06520, USA.
Corresponding author
Correspondence to Yong-hui Jiang.
Abstract
Prader-Willi Syndrome (PWS) is caused by the loss of expression of paternally expressed genes in the human 15q11.2-q13 imprinting domain. A set of imprinted genes that are active on the paternal but silenced on the maternal chromosome are intricately regulated by a bipartite imprinting center (PWS-IC) located in the PWS imprinting domain. We previously discovered that euchromatic histone lysine N-methyltransferase-2 (EHMT2/G9a) inhibitors are capable of un-silencing PWS-associated genes by restoring their expression from the maternal chromosome. Here, in mice lacking the Ehmt2 gene, we document un-silencing of the imprinted Snrpn/Snhg14 gene on the maternal chromosome in the late embryonic and postnatal brain. Using PWS and Angelman syndrome patient derived cells with either paternal or maternal deletion of 15q11.2-q13, we have found that chromatin of maternal PWS-IC is closed and has compact 3D folding confirmation. We further show that a distinct noncoding RNA (TSS4-280118) preferentially transcribed from the upstream of the PWS-IC of maternal chromosome interacts with EHMT2 and forms a heterochromatin complex in CIS on the maternal chromosome. Inactivation of TSS4-280118 by CRISPR/Cas9 editing results in unsilencing of the expression of SNRPN and SNORD116 from the maternal chromosome. Taken together, these findings demonstrate that allele-specific recruitment of EHMT2 is required to maintain the maternal imprints. Our findings provide mechanistic insights and support a model for imprinting maintenance of the PWS imprinted domain.
논문정보
- Research article
- 2025년 07월 (BRIC 등록일 2025-07-05)
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