# Epigenetic Therapy and Prader-Willi Syndrome

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $577,116

## Abstract

SUMMARY
Like most genetic disorders, no specific therapeutic intervention targets the molecular defect of Prader-Willi
syndrome (PWS), a genomic imprinting and neurobehavioral disorder that significantly affects the quality of life
of affected individuals. PWS is caused by paternal deficiency of genes in the chromosome 15q11-q13 region.
The corresponding genes on the maternal chromosome are structurally intact, but their transcription is repressed
epigenetically. The involvement of epigenetic regulation renders PWS one of the best opportunities to explore
molecular therapy. Recent reports indicate that SNORD116, a SnoRNA cluster located between the SNRPN and
UBE3A genes, is responsible for key features of PWS. Although DNA methylation and chromatin modifications
at the PWS imprinting center (PWS-IC) are believed to regulate the silent expression of PWS genes in the
maternal 15q11-q13 region, the exact mechanism remains elusive. Thus, one attractive molecular-based,
therapeutic strategy for PWS is to unsilence the expression of paternally expressed PWS genes, primarily
SNORD116, from the maternal chromosome. Because SNORD116 is processed from the long noncoding host
RNAs initiated from the PWS-IC or Snrpn promoter, we developed a drug screening system using mouse
embryonic fibroblasts (MEFs) derived from mice carrying a maternal Snrpn-EGFP fusion protein. In collaboration
with Dr. Bryan Roth (consultant for this proposal), Dr. Jiang (PI) screened 9200 small molecules and identified
and validated two compounds that can unsilence the expression of both Snrpn and Snord116 in human PWS
cells and a PWS mouse model. These compounds are selective inhibitors of histone methyltransferases (HMTs),
as defined by Dr. Jin (co-PI), whose research group is a leader in discovering selective inhibitors of HMTs.
Interestingly, in contrast with reactivation of SNRPN by DNA methylation inhibitors, these compounds reduced
the H3K9 methylation level but did not change DNA methylation of the PWS-IC. These observations together
offer new insights and opportunities to investigate the mechanism underlying the imprinted expression of PWS
genes. Our central hypothesis is that these compounds unsilence PWS candidate genes by modifying epigenetic
complexes in the PWS-IC, which will provide clinical benefits in PWS mouse models. We propose a Chromatin
Spreading Model mediated by H3K9 methylation as a mechanism of imprinted regulation of PWS genes. Our
long-term goal is to launch a clinical trial using these compounds or their derivatives in human PWS. The
complementary expertise and close collaboration between Dr. Jiang (molecular and human genetics of PWS)
and Dr. Jin (chemical biology of novel epigenetic drug development) uniquely position them to attain the specific
objectives of this study, which are to understand the mechanism by which these compounds unsilence PWS
candidate imprinted genes, to evaluate their efficacy and toxicity, and to optimize their drug-like propertie...

## Key facts

- **NIH application ID:** 9964514
- **Project number:** 5R01HD088626-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** YONG-HUI JIANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $577,116
- **Award type:** 5
- **Project period:** 2019-10-16 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964514

## Citation

> US National Institutes of Health, RePORTER application 9964514, Epigenetic Therapy and Prader-Willi Syndrome (5R01HD088626-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9964514. Licensed CC0.

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