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Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome

Nature Medicine volume 23, pages 213222 (2017) | Download Citation


Prader–Willi syndrome (PWS) is an imprinting disorder caused by a deficiency of paternally expressed gene(s) in the 15q11–q13 chromosomal region. The regulation of imprinted gene expression in this region is coordinated by an imprinting center (PWS-IC). In individuals with PWS, genes responsible for PWS on the maternal chromosome are present, but repressed epigenetically, which provides an opportunity for the use of epigenetic therapy to restore expression from the maternal copies of PWS-associated genes. Through a high-content screen (HCS) of >9,000 small molecules, we discovered that UNC0638 and UNC0642—two selective inhibitors of euchromatic histone lysine N-methyltransferase-2 (EHMT2, also known as G9a)—activated the maternal (m) copy of candidate genes underlying PWS, including the SnoRNA cluster SNORD116, in cells from humans with PWS and also from a mouse model of PWS carrying a paternal (p) deletion from small nuclear ribonucleoprotein N (Snrpn (S)) to ubiquitin protein ligase E3A (Ube3a (U)) (mouse model referred to hereafter as m+/pΔS−U). Both UNC0642 and UNC0638 caused a selective reduction of the dimethylation of histone H3 lysine 9 (H3K9me2) at PWS-IC, without changing DNA methylation, when analyzed by bisulfite genomic sequencing. This indicates that histone modification is essential for the imprinting of candidate genes underlying PWS. UNC0642 displayed therapeutic effects in the PWS mouse model by improving the survival and the growth of m+/pΔS−U newborn pups. This study provides the first proof of principle for an epigenetics-based therapy for PWS.

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We thank A. Beaudet at Baylor College of Medicine for providing the Snrpn-EGFP mice and some of the PWS cell lines; B. Philpot and M. Zlyka (University of North Carolina at Chapel Hill) for discussion. K. Konze for his advice on the ChIP experiment; S.-O. Han for his advice on blood-sample collection; C. Means and R. Rodriguiz for their assistance with neurological screening; and A. Bey for proofreading and discussion. This study is supported by grants from the US National Institutes of Health (HD077197 to Y.-H.J. and R01GM103893 to J.J.). Y.-H. Jiang is also supported by a grant from the Foundation for Prader–Willi Syndrome Research (FPWR). We thank the International Rett Syndrome Foundation and GlaxoSmithKline for providing the CNS-penetrating drug library (SMART library) and Published Kinase Inhibitor Set (PKIS), the NIMH Psychoactive Drug Screening Program (B.L. Roth) and the Michael Hooker Chair of Translational Proteomics (B.L. Roth).

Author information

Author notes

    • Yuna Kim
    •  & Hyeong-Min Lee

    These authors contributed equally to this work.


  1. Department of Pediatrics, School of Medicine, Duke University, Durham, North Carolina, USA.

    • Yuna Kim
    • , Xinyu Cao
    •  & Yong-hui Jiang
  2. Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

    • Hyeong-Min Lee
  3. Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

    • Hyeong-Min Lee
    • , Noah Sciaky
    •  & Bryan L Roth
  4. Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Yan Xiong
    •  & Jian Jin
  5. Department of Neurobiology, School of Medicine, Duke University, Durham, North Carolina, USA.

    • Samuel W Hulbert
    •  & Yong-hui Jiang
  6. Department of Pathology, School of Medicine, Duke University, Durham, North Carolina, USA.

    • Jeffrey I Everitt
  7. Program in Neuroscience, Division of Chemical Biology and Medicinal Chemistry, and NIMH Psychoactive Drug Screening Program, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

    • Bryan L Roth
  8. Program in Genetics and Genomics, School of Medicine, Duke University, Durham, North Carolina, USA.

    • Yong-hui Jiang


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Y.K. and H.-M.L. designed and performed the experiments and wrote the manuscript. Y.X. and J.J. provided G9a inhibitors and epigenetic-small-molecule libraries. N.S. performed the Cell Profiler. B.L.R. supervised the high-content screening and provided small-molecule libraries. X.C. supported cell culture and mouse-colony maintenance. S.W.H. supported mouse-colony maintenance and neurological analysis. J.I.E. performed histopathological analysis. Y.J. designed the experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Bryan L Roth or Yong-hui Jiang.

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