Snord116-dependent diurnal rhythm of DNA methylation in mouse cortex

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. A major genetic effect on rhythmic methylation was identified in a mouse Snord116 deletion model of the imprinted disorder Prader-Willi syndrome (PWS). Of the >23,000 diurnally rhythmic CpGs identified in wild-type cortex, 97% lost rhythmic methylation in PWS cortex. Circadian dysregulation of a second imprinted Snord cluster at the Temple/Kagami-Ogata syndrome locus was observed at the level of methylation, transcription, and chromatin, providing mechanistic evidence of crosstalk. Genes identified by diurnal epigenetic changes in PWS mice overlapped rhythmic and PWS-specific genes in human brain and were enriched for PWS-relevant obesity 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.Daily and seasonal cycles of light, temperature, and feeding govern energy and activity of organisms from all branches of life. These environmental and metabolic inputs play an important role in the synchronization of the core circadian clock with the rhythmic patterns of many physiological and behavioral processes in peripheral tissues [1][2][3] . The genetically encoded circadian cycle and the environmentally regulated diurnal cycle are integrated by a complex regulatory feedback network which acts at the chromatin, transcriptional, and translational levels to coordinate biological and environmental rhythms [4][5][6] . In mammals, the core circadian clock resides in the suprachiasmatic nucleus of the hypothalamus; however, almost half of all transcripts, both protein-coding and non-coding, exhibit diurnal rhythms in one or more peripheral tissues 7,8 . The epigenetic mechanisms involved in the diurnal rhythms of the cerebral cortex are less well characterized; however, increasing evidence indicates a role for DNA methylation in these rhythms. In contrast to the historically accepted view of DNA methylation as a stably maintained epigenetic mark, approximately 6% (25,476) of CpG sites assayed by 450k array are dynamically regulated throughout diurnal and seasonal cycles 9 . This epigenetic plasticity plays an important role in circadian entrainment and the resiliency of the circadian clock to changes in the diurnal environment [10][11][12] . Studies of shift work have demonstrated that sleep deprivation (SD) results in the epigenetic and transcriptional dysregulation of core circadian genes and increased risk for adverse metabolic phenotypes and cancer 13,14 . The epigenetic and metabolic dysregulation associated with SD in healthy individuals provides a basis for understanding these characteristics in the context of neurodevelopmental disorders, which often share a core sleep phenotype among their unique distinguishing f...

Expression Changes in Epigenetic Gene Pathways Associated With One‐Carbon Nutritional Metabolites in Maternal Blood From Pregnancies Resulting in Autism and Non‐Typical Neurodevelopment

“…The complementary co‐expression network analysis further revealed a module of 224 co‐expressed genes in maternal blood showing an association with folic acid and 5‐MeTHF levels in the opposite direction from ASD risk that could not be explained by cell type differences. Interestingly, these ASD and nutrient associated genes were functionally enriched for DNA methylation binding and methylation‐dependent chromatin silencing, consistent with prior DNA methylation changes observed in ASD [Coulson et al, 2018; Mordaunt et al, 2020; Vogel Ciernia et al, 2019; Zhu et al, 2019] as well as ASD‐like syndromes associated with methyl binding proteins [Cukier et al, 2012; Cukier et al, 2010]. MBD3L , which has methyl‐binding function, is predicted to assist with demethylation reactions and functions as a transcriptional repressor [Fouse, Nagarajan, & Costello, 2010; Mungall, 2002; Zhou et al, 2019].…”

Cognitive deficits in the Snord116 deletion mouse model for Prader-Willi syndrome

“…Earlier research using the same Snord116 +/− mutation mice reported disrupted circadian rhythms, sleep-wake cycles, frontal cortical transcriptional and epigenetic regulation, as well as reduced forebrain neuronal and cerebellar cellular sizes, which could mechanistically contribute to the behavioral phenotypes reported (Burnett et al, 2017; Coulson et al, 2018; Lassi, Priano, et al, 2016). Other in vivo model systems of PWS deleted the entire critical imprinting center and reported low locomotor abilities and impairments in the frontal cortical dependent five choice serial reaction time task (Relkovic et al, 2010).…”

Baby food and bedtime: Evidence for opposite phenotypes from different genetic and epigenetic alterations in Prader-Willi and Angelman syndromes

“…Powell et al 75 identified dysregulation of about 6000 diurnally regulated genes in the mouse cortex, including dysregulation of the pacemaker genes such as Cry1, Clock, Per2 and Mtor as well as increased expression of Ube3a, which regulates the oscillatory pattern of Bmal1 via ubiquitination. 71 Coulson et al 76 further showed that loss of expression for Snord116 led to a pattern of shifted diurnal methylation characterized by losses during the light phase and increased diurnal methylation during the dark phase. The authors suggest that the gene expression of epigenetic and circadian regulators is increased in the model mice during the light phase, which may lead to prolonged accumulation of these proteins into the dark phase, resulting in the shifted methylation pattern.…”