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 properties. The proposed study is significant because it will provide novel insight into the molecular mechanism underlying genomic imprinting in PWS and lead to the development of a therapeutic intervention for the disease.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Therapeutic Approaches to Genetic Diseases Study Section (TAG)
Program Officer
King, Tracy
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
New Haven
United States
Zip Code
Babault, Nicolas; Allali-Hassani, Abdellah; Li, Fengling et al. (2018) Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT). J Med Chem 61:1541-1551
Chiarella, Anna M; Wang, Tiffany A; Butler, Kyle V et al. (2018) Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers. J Vis Exp :
Wang, Dong-Yao; Kosowan, Joel; Samsom, James et al. (2018) Inhibition of the G9a/GLP histone methyltransferase complex modulates anxiety-related behavior in mice. Acta Pharmacol Sin 39:866-874
Morini, Marco F; Giampietro, Costanza; Corada, Monica et al. (2018) VE-Cadherin-Mediated Epigenetic Regulation of Endothelial Gene Expression. Circ Res 122:231-245
Butler, Kyle V; Chiarella, Anna M; Jin, Jian et al. (2018) Targeted Gene Repression Using Novel Bifunctional Molecules to Harness Endogenous Histone Deacetylation Activity. ACS Synth Biol 7:38-45
Duffney, Lara J; Valdez, Purnima; Tremblay, Martine W et al. (2018) Epigenetics and autism spectrum disorder: A report of an autism case with mutation in H1 linker histone HIST1H1E and literature review. Am J Med Genet B Neuropsychiatr Genet 177:426-433
Chung, Leeyup; Bey, Alexandra L; Towers, Aaron J et al. (2018) Lovastatin suppresses hyperexcitability and seizure in Angelman syndrome model. Neurobiol Dis 110:12-19
Chung, Changuk; Ha, Seungmin; Kang, Hyojin et al. (2018) Early Correction of N-Methyl-D-Aspartate Receptor Function Improves Autistic-like Social Behaviors in Adult Shank2-/- Mice. Biol Psychiatry :
Pellock, Samuel J; Creekmore, Benjamin C; Walton, William G et al. (2018) Gut Microbial ?-Glucuronidase Inhibition via Catalytic Cycle Interception. ACS Cent Sci 4:868-879
Zhang, Chengwei; Han, Xiao-Ran; Yang, Xiaobao et al. (2018) Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK). Eur J Med Chem 151:304-314

Showing the most recent 10 out of 14 publications