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Epigenetic therapy of Prader-Willi syndrome

Yuna Kim1, Sung Eun Wang1, Yong-Hui Jiang2

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

Translational Research : the Journal of Laboratory and Clinical Medicine
|March 25, 2019
PubMed

Insights

Prader-Willi syndrome (PWS) is a genetic disorder caused by missing paternal genes. Epigenetic therapy using EHMT2/G9a inhibitors reactivated these genes, offering a potential treatment for PWS.

Area of Science:

  • Genetics
  • Epigenetics
  • Neurobiology

Background:

  • Prader-Willi syndrome (PWS) is a complex neurobehavioral disorder resulting from the deficiency of paternally expressed genes on chromosome 15q11-q13.
  • Maternal genes in the same region are transcriptionally silenced via epigenetic mechanisms, despite being structurally intact.

Purpose of the Study:

  • To explore the potential of epigenetic-based therapy for PWS by reactivating silenced maternal genes.
  • To identify small molecules capable of restoring the expression of PWS-related genes.

Main Methods:

  • Investigated the role of SETDB1 and ZNF274 in gene reactivation in PWS patient-derived induced pluripotent stem cells (iPSCs) and neurons.
  • Utilized high-content screening of small molecule libraries in transgenic mouse cells to identify EHMT2/G9a inhibitors.
  • Tested identified inhibitors in PWS patient-derived fibroblasts and a PWS mouse model.

Main Results:

  • Inactivation of SETDB1 and ZNF274 reactivated SNRPN and SNORD116 clusters from maternal chromosomes in PWS iPSCs and neurons.
  • EHMT2/G9a inhibitors successfully reactivated paternally expressed SNRPN and SNORD116 from the maternal chromosome in PWS cells and a mouse model.
  • Treatment with an EHMT2/G9a inhibitor ameliorated perinatal lethality and failure to thrive phenotypes in the PWS mouse model.

Conclusions:

  • Demonstrated proof-of-principle for an epigenetic-based therapeutic strategy for Prader-Willi syndrome.
  • Identified EHMT2/G9a inhibitors as promising candidates for PWS treatment by targeting epigenetic silencing.
  • Findings open new avenues for developing treatments for PWS by manipulating epigenetic mechanisms.

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