Sufficient sleep is essential for optimal metabolic, cognitive, and mental health. Circadian rhythms affecting sleep behavior are genetically determined, but environmentally entrained by external cues such as light exposure. Circadian entrainment is predicted to be established by poorly understood epigenetic mechanisms that allow mammals to adapt their metabolism to the environment. Distinct patterns of sleep and diurnal metabolism have evolved within mammals, coinciding with the acquisition of SNORD116 small nucleolar RNA (snoRNA) repeats in the Prader-Willi syndrome (PWS) locus. The PWS locus is imprinted, meaning that genes expressed only on the paternal but not the maternal chromosome 15q11-q13 region are causative. PWS is caused by the loss of two types of noncoding RNAs encoded by SNORD116. First, SNORD116 snoRNAs localize to the nucleolus in maturing neurons and impact rRNA and nucleolar maturation. Second, the host gene exons flanking the SNORD116 snoRNAs are spliced and retained in the nucleus as a long noncoding RNA, forming a large RNA cloud structure that regulates transcription of circadian transcription factors, DNA methylation, and metabolism. The intronic sequences of SNORD116 exhibit high GC skew, promoting the formation of DNA:RNA hybrid structures called R-loops. R-loops promote chromatin decondensation, slow transcriptional progression, and protect from DNA methylation. Interestingly, maternal overexpression of a similarly structured large imprinted snoRNA cluster on chromosome 14 causes PWS-related Temple syndrome, and published evidence supports the cross-regulation of these two imprinted loci. In our recent analyses of epigenetic changes associated with circadian rhythmicity and the Snord116 locus, >23,000 rhythmic methylated CpGs were observed in wild-type mouse cortex, of which 97% were lost or time-shifted in Snord116+/- littermates. These Snord116-impacted methylation enhancers and promoters regulated genes with functions highly enriched for circadian entrainment and body weight, including genes within the Temple syndrome locus. In this proposal, we seek to understand the role of Snord116 in circadian entrainment and the epigenetic mechanisms underlying Snord116 regulation of rhythmic circadian cycles of gene expression genome-wide, with a focus on imprinted snoRNA loci. The results of these experiments are expected to expand functional knowledge of imprinted noncoding RNAs and potentially enable future epigenetic therapies for imprinting disorders. In addition, determining how noncoding RNAs regulate circadian epigenetic rhythms and metabolism during sleep/wake cycles to modify phenotypes is an emerging basic science field. These studies may therefore have profound future impacts on improving sleep, mental health, and weight problems that affect almost all humans.

Public Health Relevance

Prader-Willi syndrome (PWS) is a debilitating neurodevelopmental disorder causing intellectual disabilities, obsessive-compulsive disorders, disrupted sleep patterns, and a metabolic syndrome often leading to obesity. PWS individuals also show increased risk for autism- spectrum disorders, making understanding the molecular genetics of PWS relevant to understanding the more common causes of sleep, metabolic, and neuropsychiatric disorders. This proposal seeks to understand how genes within the PWS locus regulate circadian entrainment of activity and metabolic cycles to light cues in a mouse model.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD098038-03
Application #
10075803
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
King, Tracy
Project Start
2019-01-15
Project End
2023-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
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