Research byJanine LaSalle, professor in the Department of Medical Microbiology and Immunology, the UC Davis Genome Center and MIND Institute, was published today in Nature Communications. LaSalle describes her work and the importance of the research below:
Q: What role do sleep disturbances play in neurodevelopmental disorders?
Sufficient sleep is essential for optimal metabolic, cognitive, and mental health. Almost all children affected by neurodevelopmental disorders, including autism spectrum disorders (ASD), have sleep disturbances, but it is often difficult to separate cause from consequence. A recent epidemiology study showed that the relationship between ASD and sleep problems was not bidirectional, in that they co-occur with the rise of autistic traits in early childhood and therefore are not simply a consequence.
Circadian rhythms affecting sleep behavior are genetically determined, but environmentally entrained by external cues such as light exposure and meal times. Therefore, the factors influencing sleep disturbances act at the interface of genes and environment, much like the risk factors for ASD. DNA methylation is a modification on top of the DNA four-letter code that reflects interactions between genes and environment important for sleep and neurodevelopmental disorders. Methylation primarily occurs at CpG sites (cytosine-guanine) in DNA of mammals.
Q: What did you hope to learn in this research project?
Human chromosome 15q11-q13 is associated with multiple neurodevelopmental disorders, including Prader-Willi syndrome, a complex genetic condition characterized by intellectual impairment, learning disabilities, behavior problems and distinctive facial features. Our prior work showed that the 15q Snord116 genes causing Prader-Willi syndrome regulate circadian genes and daily changes in brain metabolism. In the current study, we asked if DNA methylation alterations may be different by time of day in a Prader-Willi mouse model.
Q: How did you conduct the study?
We utilized a mouse model of Prader-Willi syndrome that has a small paternal deletion of Snord116 genes that are deleted in human patients. We took brains from the mutant and wild-type littermates at seven different time points during a 24 hour day. We used DNA isolated from cerebral cortex to examine DNA methylation differences by time and genotype. We also isolated RNA to look at gene expression and fixed tissue sections to examine the chromosomal dynamics in situ.
Q: What were your key findings?
We found ~23,000 CpG sites (~0.4% of all possible CpG sites) in the genome to have a light cycle rhythmicity in wild-type mice. In the Prader-Willi mouse model, however, 97% of these light rhythmic methylation events were either lost or time-shifted to the dark cycle. Using the combined analysis of rhythmic gene expression and methylation, we identified genes that have already known associations with body weight and metabolism, as well as circadian entrainment, which is the ability to adjust to a new time zone or light cycle.
Q: How do these findings help in the potential treatment of these problems?
Chronotherapy is a relatively new field of medicine that seeks to treat illnesses by taking into account and/or adjusting the body’s natural rhythms and cycles. Our study suggests that chronotherapeutic approaches may be useful in PWS treatments. In addition, these results add to an emerging literature on the links between sleep and circadian rhythms on maintaining mental, cognitive, and metabolic health, which is relevant to all humans.