Like most genetic disorders, no specific therapeutic intervention targets the specific molecular defect of Prader- Willi syndrome (PWS), a genomic imprinting and neurobehavioral disorder. PWS is caused by paternal deficiency of genes in the chromosome 15q11-q13 region. The corresponding genes in the maternal chromosome are structurally intact, but their transcription is repressed epigenetically. The involvement of epigenetic repression renders PWS as one of the best opportunities to explore molecular therapy. Recent reports indicate SnoRNA, clusters including HBII-85 (SNORD116) between the SNRPN and UBE3A genes, is responsible for key features of PWS including childhood obesity, hypogonadism, hyperphagia, and developmental delay. Epigenetic mechanisms, including DNA methylation and chromatin modifications at the PWS imprinting center region (PWS-ICR), are involved in regulating the paternal-specific expression of genes including SNRPN and SnoRNAs in the 15q11-q13 region. The imprinting domain in the 15q11-q13 region is highly conserved in mice. The expression of SnoRNA clusters is processed from continuous transcripts initiated from the PWS-ICR/promoter bound CpG island of SNRPN. DNA methylation can activate the expression of the SNRPN gene from the silent maternal chromosome in cultured cells of PWS patients and mouse models, but its clinical utility is limited by the concern of the genome wide effect of these drugs. These observations, however, strongly support a approach to unsilence/activate the expression of SnoRNAs from maternal chromosome through an epigenetic mechanism. Because the SnoRNAs are non-coding, we propose to use embryonic fibroblasts (MEFs) from mice carrying Snrpn-EGFP fusion protein as screening tool. Drugs that activate the Snrpn-EGFP are expected to have the same impact on the SnoRNAs. In collaboration with Dr. Bryan Roth (Director of NIMH Psychoactive Drug Screening Program), we have completed the first phase screen and identified several candidate drugs. We have showed that a histone methyltransferase inhibitor activated the expression of Snrpn and SnoRNAs from the maternal chromosome in cultured PWS cells. Using the same strategy, Dr. Roth's team also identified a FDA approved drug that activates the Angelman syndrome Ube3a gene from paternal chromosome in vivo. The long term goal of our project is to develop a therapeutic intervention targeted to the specific epigenetic defects of PWS. The central hypothesis is that a small molecule can modulate the epigenetic modification in the PWS-ICR and lead to the activation of the silenced PWS candidate genes from the maternal chromosome. The specific objective is to identify and characterize small molecules that activate the expression of Snrpn and SnoRNAs from the maternal chromosome by performing high-content small molecule screening using maternal Snrpn-EGFP as a marker. The proposed study is significant because it will lead to the development of a therapeutic intervention in PWS and provide the novel insight for molecular mechanism underlying the genomic imprinting.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Therapeutic Approaches to Genetic Diseases (TAG)
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Oster-Granite, Mary Lou
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Duke University
Schools of Medicine
United States
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