Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with a known genetic etiology, but a complex epigenetic basis. PWS is an imprinted disorder, meaning that loss of genes expressed only on the paternal but not the maternal chromosome 15q11- q13 region cause disease. Furthermore, unlike genetic mutations that affect protein- coding genes, the smallest genetic deletions causing PWS only affect noncoding transcripts of RNA. At the heart of the minimally deleted region in PWS are two types of noncoding RNAs. First, the SNORD116 small nucleolar RNAs (snoRNAs) localize to the nucleolus in maturing neurons and impact rRNA and nucleolar maturation. Second, the host gene exons (116HG) surrounding the SNORD116 snoRNAs are spliced and nuclear retained as a long noncoding RNA (lncRNA), forming a large RNA cloud-like structure that regulates diurnally expressed transcription and metabolism. The intronic sequences with high GC skew form DNA:RNA hybrid structures called R-loops that promote chromatin decondensation and slow transcriptional progression of the antisense transcript to the Angelman syndrome (AS) gene UBE3A. In this proposal, we seek to answer three major unanswered questions regarding the molecular pathogenesis of PWS. 1) What are the major genetic and cellular components required for noncoding RNA localization and function leading to the PWS phenotypes? 2) What is the influence of diurnal time on the cross-regulatory mechanisms of the PWS locus? 3) Could alterations to light/dark cycles and temperature be used to optimize a rapamycin therapy in the PWS mouse model? The results of these experiments are expected to improve understanding of the functional role of the lncRNAs at the heart of the PWS locus.
Prader-Willi syndrome (PWS) is a debilitating disorder causing intellectual disabilities, obsessive-compulsive disorders, and an uncontrolled appetite often leading to obesity. PWS individuals also show increased risk for autism-spectrum disorders, making comprehension of the molecular genetics of PWS relevant to understanding the more common causes of autism, obesity, and neuropsychiatric disorders affecting humans. This proposal addresses fundamental questions of how the minimal genetic region in PWS is required for diurnal metabolism and neuronal maturation using molecular and genomic approaches in mouse models as well as human brain tissues. Results from these investigations are expected to provide insight into the molecular pathogenesis of PWS and may enable improved therapy for PWS by timed rapamycin treatments, phototherapy, and/or noncoding RNA based therapies. In addition, the significance of the proposed studies extends beyond PWS, as improved understanding of noncoding RNAs regulating sleep and diurnal cycles of metabolism are expected to be relevant to treatment of more common disorders of sleep, metabolism, and obesity.
| Coulson, Rochelle L; Yasui, Dag H; Dunaway, Keith W et al. (2018) Snord116-dependent diurnal rhythm of DNA methylation in mouse cortex. Nat Commun 9:1616 |
