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 genes expressed only on the paternal but not the maternal chromosome 15q11-13 region are responsible. 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 HBII-85/SNORD116 small nucleolar RNAs (snoRNAs) localize to the nucleolus in maturing neurons and impact rRNA and nucleolar maturation. Second, the host gene exons surrounding the HBII-85/SNORD116 snoRNAs are spliced and nuclear retained as a long noncoding RNA (lncRNA), forming a large RNA cloud-like structure that increases in size with neuronal maturity. While most of the focus in the PWS field has been on understanding the function of the snoRNAs and protein coding genes, the host snoRNA-lncRNA may be of equal if not greater importance to understanding and treating the underlying neurodevelopmental defect in PWS. In this proposal, we seek to answer three major unanswered questions regarding the molecular pathogenesis of PWS. 1) What is the mechanistic basis for chromatin decondensation specifically in mature neurons? 2) Which ncRNA is responsible for the PWS phenotype, the snoRNAs or the host lncRNA? 3) What are the genetic and mechanistic bases of the mouse/human phenotypic differences associated with the PWS locus deficiency and duplication? The approaches include novel fluorescence in situ methods for combined detection of R-loops, ncRNAs, and chromatin decondensation in mouse and human brain and novel mouse-human hybrid neuronal cell lines and human PWS induced pluripotent cell derived neurons. The results of these experiments are expected to improve understanding of functional role of the lncRNAs at the heart of the PWS locus and potentially enable future epigenetic therapies for PWS.
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 understanding the molecular genetics of PWS potentially relevant to understanding the more common causes of autism, obesity, and mental disorders affecting humans. This proposal addresses the major questions of how the minimal genetic deletions in PWS on noncoding genes are required for early postnatal growth and neuronal maturation using mouse models as well as human brain tissues and stem cell derived neurons. Results from these investigations are expected to improve understanding of the genetic basis of PWS and may enable epigenetic therapy for PWS by reactivating inactive transcripts through noncoding RNA based therapies.
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| Vogel Ciernia, Annie; LaSalle, Janine (2016) The landscape of DNA methylation amid a perfect storm of autism aetiologies. Nat Rev Neurosci 17:411-23 |
| Crawley, Jacqueline N; Heyer, Wolf-Dietrich; LaSalle, Janine M (2016) Autism and Cancer Share Risk Genes, Pathways, and Drug Targets. Trends Genet 32:139-146 |
| Powell, Weston T; LaSalle, Janine M (2015) Epigenetic mechanisms in diurnal cycles of metabolism and neurodevelopment. Hum Mol Genet 24:R1-9 |
| LaSalle, Janine M; Reiter, Lawrence T; Chamberlain, Stormy J (2015) Epigenetic regulation of UBE3A and roles in human neurodevelopmental disorders. Epigenomics 7:1213-28 |
| LaSalle, Janine M (2013) Epigenomic strategies at the interface of genetic and environmental risk factors for autism. J Hum Genet 58:396-401 |
| LaSalle, Janine M; Powell, Weston T; Yasui, Dag H (2013) Epigenetic layers and players underlying neurodevelopment. Trends Neurosci 36:460-70 |
| Lasalle, Janine M (2013) Autism genes keep turning up chromatin. OA Autism 1:14 |
| Powell, Weston T; Coulson, Rochelle L; Gonzales, Michael L et al. (2013) R-loop formation at Snord116 mediates topotecan inhibition of Ube3a-antisense and allele-specific chromatin decondensation. Proc Natl Acad Sci U S A 110:13938-43 |
| Powell, Weston T; Coulson, Rochelle L; Crary, Florence K et al. (2013) A Prader-Willi locus lncRNA cloud modulates diurnal genes and energy expenditure. Hum Mol Genet 22:4318-28 |
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