Abstract
Rhythmic oscillations of physiological processes depend on integrating the circadian clock and diurnal environment. DNA methylation is epigenetically responsive to daily rhythms, as a subset of CpG dinucleotides in brain exhibit diurnal rhythmic methylation. Here, we show a major genetic effect on rhythmic methylation in a mouse Snord116 deletion model of the imprinted disorder Prader–Willi syndrome (PWS). More than 23,000 diurnally rhythmic CpGs are identified in wild-type cortex, with nearly all lost or phase-shifted in PWS. Circadian dysregulation of a second imprinted Snord cluster at the Temple/Kagami-Ogata syndrome locus is observed at the level of methylation, transcription, and chromatin, providing mechanistic evidence of cross-talk. Genes identified by diurnal epigenetic changes in PWS mice overlapped rhythmic and PWS-specific genes in human brain and are enriched for PWS-relevant phenotypes and pathways. These results support the proposed evolutionary relationship between imprinting and sleep, and suggest possible chronotherapy in the treatment of PWS and related disorders.
Highlights
Rhythmic oscillations of physiological processes depend on integrating the circadian clock and diurnal environment
We identified genes significantly enriched for Prader–Willi syndrome (PWS)-relevant phenotypes of body mass index (BMI) and circadian-entrained metabolic pathways from the genes that lost rhythmic DNA methylation and gained expression in PWS mice
Due to the nocturnal rhythm of mice and differences in PWS phenotype between mice and humans, we evaluated the significance of our mouse study using comparative analyses across species for phenotype and rhythmicity
Summary
Rhythmic oscillations of physiological processes depend on integrating the circadian clock and diurnal environment. Studies of a PWS mouse model (Snord116+/−) carrying a ~150 kb paternal deletion of Snord[116] revealed a specific role for 116HG in the diurnal regulation of genes with circadian, metabolic, and epigenetic functions[28,29] These changes were phase specific, with transcriptional and metabolic dysregulation observed predominately during the light phase[28]. The loss of Snord[116] expression in PWS results in the upregulation of genes in the TS locus in mouse whole cerebral cortex, indicating that the two loci may interact through a cross-regulatory network[28] In support of this hypothesis, IPW from the PWS locus has been shown to regulate the TS locus in an induced pluripotent stem cell line of PWS39. The TS locus is enriched for these sites of PWSdisrupted diurnal DNA methylation and exhibits time-disrupted chromatin changes opposite in diurnal time to the light-specific chromatin changes of the PWS locus
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