# Imprinted snoRNA loci and circadian entrainment

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $492,915

## Abstract

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.

## Key facts

- **NIH application ID:** 10075803
- **Project number:** 5R01HD098038-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Janine M LaSalle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $492,915
- **Award type:** 5
- **Project period:** 2019-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075803

## Citation

> US National Institutes of Health, RePORTER application 10075803, Imprinted snoRNA loci and circadian entrainment (5R01HD098038-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10075803. Licensed CC0.

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