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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS076263-03
Application #
8507813
Study Section
Special Emphasis Panel (ZRG1-BDCN-J (02))
Program Officer
Mamounas, Laura
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$320,324
Indirect Cost
$109,230
Name
University of California Davis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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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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