Dysregulation of Circadian Rhythm Gene Expression in Cystic Fibrosis Mice

Abstract

Cystic fibrosis (CF) is autosomal recessive disease that affects multiple body systems. CF patients often experience sleep disturbances, altered sleep patterns, and sleep apnea. Sleep in mammals is controlled in part by circadian clock genes, including Clock, Bmal1, Period1, Period2, Cryptochrome1, and Cryptochrome2 . The purpose of this study was to gain a better understanding of the biological underpinnings of disordered sleep experienced in CF. To accomplish this, we evaluated circadian clock gene expression profiles in CF and wildtype mice, divided into two subgroups each based on sleep condition. One subgroup of each genotype was permitted to maintain their sleep-wake cycle while the other was deprived of sleep for six hours prior to sacrifice. Brain, skeletal muscle, jejunum, colon, lung and adipose tissues were collected from each mouse. Quantitative polymerase chain reaction (PCR) was used to quantify expression of Clock, Bmal1, Period1, Period2, Cryptochrome1 and Cryptochrome2, and expression levels were compared between study groups. Our comparisons showed distinct differences between the CF groups and the wildtype groups under both sleep conditions. Additionally, we found the CF mice that had been sleep deprived had severely dysregulated expression of all measured genes in the lung apart from Cry1 . Our findings suggest that (1) disordered sleep in CF may be caused by circadian system dysregulation and (2) the loss of the cystic fibrosis transmembrane conductance regulator (CFTR) is a causative factor in the dysregulated circadian clock gene expression profiles of CF mice.

Cystic Fibrosis and Sleep Circadian Rhythms

“…It has always been widely assumed that CF-related symptoms are the primary cause of sleep disruption in CF patients, as described above [24]. However, recent studies implicate circadian rhythm disturbances and CFTR dysfunction as potential causes of sleep disturbances in CF patients [34].…”

“…Barbato et al collected tissue samples from both CF-afflicted and healthy mice counterparts and compared tissue samples obtained from both groups in both standard and sleep-deprived states [34]. They found that the CF group had a significant expression of dysregulated circadian clock genes, which they assumed was due to loss of CFTR functionality [21].…”

“…The relationship between the CFTR gene and its role in regulating the circadian pattern may have clinical implications. Studies have reported alteration in circadian clock gene expression and modulation of lung function as a whole [34]. Limited information on impaired sleep's effect on CF patients' immune system, brain function, and metabolic activity warrants further research in this area.…”

Tubulin Polymerization Promoting Protein Affects the Circadian Timing System in C57Bl/6 Mice

“…That rhythmic expression is regulated by a self-contained feedback loop which is integral to the function of the CTS. Dysfunction of the system, caused by endogenous or exogenous factors, has been linked to many disease processes, including disordered sleep, anxiety and depression, cardiac disease, immune dysfunction, and many others [ 4 5 ].…”

“…Many genes and their protein products have been associated with the CTS, some of which include Clock, Bmal1, Period1, Period2, Cryptochrome1 , and Cryptochrome2 [ 5 6 ]. The core molecular functionality of the CTS, including its unique process of self-regulating gene expression, has been well described [ 4 7 8 ].…”