Up All Night and Asleep All Day: How Jet Lag Impacts Epigenetics
Anyone who has ever dragged themselves off of a red-eye flight, understands the exhaustion of jet lag. Depending on how far you’ve traveled, the effects of jet lag can last from days to weeks, leading to sleepless nights and tired days as your body attempts to reset its circadian clock. Research has shown that frequently disrupting the body’s circadian rhythm can lead to increased susceptibility to disease, including cardiovascular issues and cancer [1-3]. It has been suggested that the stress of altered circadian rhythms, for example from jet lag, may affect the epigenetic landscape of cells thus leading to adverse disease outcomes later in life . To investigate the epigenetic effect of jet lag, Chaves and colleagues subjected pregnant mice to jet lag and assessed its effect on their offspring.
To understand how jet lag experienced by the mother mouse affected the development of her pups, the authors exposed pregnant mice to one of three conditions: no jet lag (CTL), advanced jet lag (ADV) which mimics east-bound jet lag, or delayed jet leg (DEL) for west-bound jet lag. When they assessed weight of the pups over time, the authors found that pups of the ADV or DEL mothers had a significant delay in growth with pups from ADV mothers never reaching their target weight.
While jet lag experienced by their mothers impacted the growth of the pups, the authors next wondered how well the pups themselves were able to recover from jet lag. Intriguingly, they found that pups from ADV mothers recovered from ADV jet lag much faster than pups from CTL mothers. The same result was seen for pups from DEL mothers, which recovered faster from DEL jet lag than CTL mice did. Overall, the authors saw that while gestational jet lag impairs growth, it also helps the pups recover from jet lag if it’s in the same direction their mothers were exposed to.
Digging deeper into the biological effects of jet lag, the authors looked at how jet lag in the pups’ mothers affected the bone structure and strength of their pups. Interestingly, the authors saw no difference in bone strength between pups from DEL or CTL mothers, but they saw a clear reduction in bone size in pups from ADV mothers. To ask what might be causing the reduction in bone size, the authors removed bone-marrow from the pups and asked if there was an effect on osteoblast or osteoclast function, the cells that promote bone formation. They found that bone marrow from pups from ADV mothers had decreased osteoblast differentiation, suggesting that reduced osteoblast function leads to the reduced bone size seen in the ADV pups.
Because circadian rhythm disease can result in cardiovascular problems, the authors next looked at the effect of jet lag on the heart. First looking at the structure of the heart by histology, the authors saw that ADV pups had an enlarged left ventricle cavity and thinner left and right ventricle walls. DEL pups also had a thinner right ventricle wall when compared to CTL mice. When the authors looked at the heart structure in more detail, they saw evidence of fibrosis in both DEL and ADV pups but not CTL pups, and they found that DEL and ADV pups had smaller heart muscle cells compared to CTL pups. Additionally, when they looked at heart function, they saw that the percentage of blood that was being pumped through the heart in both DEL and ADV pups was reduced by 30% compared to CTL pups, indicating that DEL and ADV jet lag in pregnant mice affects both the structure and function of the heart in the pups.
Next the authors asked if jet lag in mothers affected DNA methylation in the pups. Reasoning that jet lag would have affected the timing of when the mothers ate, which would have impacted their metabolic functions , the authors used MeD-seq  to assess genome-wide methylation levels in pup liver tissue. They found that over 500 promoter regions were hypermethylated in the ADV and DEL pups compared to CTL pups. Using Gene Ontology analysis to identify the biological processes that these regions were involved in, they found that, interestingly, all of the processes were controlled by the micro-RNA cluster, miR17-92. The authors next asked if there were differences in DNA methylation at regions of the gene body, outside of the promoter region. Looking specifically at circadian rhythm genes, they found that the genes Creb5, Crtc1, and CK2a were all differentially methylated.
To see if the differential methylation correlated with differential gene expression, the authors performed RT-qPCR on circadian rhythm genes and found that the genes Bmal1, Clock, Cry2, and Creb5 were differentially expressed in liver of ADV and DEL pups. The expression levels of the miR17-92 cluster were only marginally different in the jet lag pups compared to the CRL pups. When the authors looked at the expression of P21, a target of miR17-92, in heart tissue, however, they did see a significant increase in the percentage of P21 positive cells in the ADV and DEL pups. This result suggests that altered expression of miR17-92 in heart tissue might be involved in the adverse effects observed in ADV and DEL mice compared to the CTL pups.
Overall, this study shows that jet lag experienced by pregnant mice affects the health of their offspring, in overall growth and bone and heart health. Gestational jet lag also results in altered DNA methylation which correlates with altered expression of circadian rhythm genes in the pups, possibly leading to their observed health defects. While more work is needed to investigate the effect of jet lag on altered gene expression and disease state, this study demonstrates the deleterious effects of jet lag beyond a few weeks of upset sleep.
Original Article: Chaves I, van der Eerden B, Boers R, Boers J, Streng AA, Ridwan Y, Schreuders-Koedam M, Vermeulen M, van der Pluijm I, Essers J, Gribnau J, Reiss IKM, van der Horst GTJ (2019). Gestational jet lag predisposes to later-life skeletal and cardiac disease. Chronobiol Int, 1-15. doi: 10.1080/07420528.2019.1579734.
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