Sleep Deprivation on a Genetic Level

By Ng Chi Wai, Jessie

We all know night owls – people who would stay up until 3 a.m. to cram in all their coursework, or perhaps for no reason at all. Some of us are night owls by choice, some are not. Around 15-20% of workers in Europe and the USA are required to take occasional night shifts even though chronic sleep deprivation is known to be detrimental to health.

Research on Sleep Deprivation

In a study using rat models, it was found that long-term sleep deprivation produces significant physiological changes such as increased energy expenditure, decreased body weight and even death after 2-3 weeks. Microarrays were used to screen over 26 000 transcripts in the cerebral cortex of rats that have been sleep-deprived for 7 days (Chronic sleep deprivation). 75 of these transcripts were found to have increased in expression compared to control rats that were spontaneously awake or acutely sleep deprived (a few hours). These transcripts with increased expression encoded immunoglobulins, stress response proteins, minoxidil sulfotransferase, globins and cortistatin. There were also 28 transcripts whose expressions had been suppressed after chronic sleep deprivation, 16 of which were directly linked to sleep loss, including genes encoding for type I procollagen and dihydrolipoamide acetyltransferase. 

An interesting observational study conducted by the University of Hong Kong compared baseline blood samples from healthy doctors with adequate sleep and participants that were acutely sleep-deprived. This study showed that disrupted sleep is associated with DNA damage (Cheung et al., 2018). Gene expression data showed that those who are acutely sleep-deprived have lower expression in DNA repair genes, including OGG1 and ERCC1 (Cheung et al., 2018), which are involved in nucleotide excision repair and base excision repair, and decreased plasma antioxidant capacity. Reduced expression of these genes is linked to accumulation of DNA damage and accelerated mutation and tumorigenesis DNA breaks and oxidized purines also seem to be more prominent in participants that were sleep deprived than in blood samples from participants in the control group (Cheung et al., 2018). This suggests that sleep deprivation impairs the activity of DNA repair.

How Sleep Influences Chromosome Dynamics

Sleep is crucial to DNA repair. In a study using zebrafish larvae model, it was found that behavioral immobility and reduced sensory input during sleep could favor behavioral-state-dependent cellular processes in neurons. The zebrafish larvae’s chromosome dynamics, which refers to the coupled spatial movements of loci when subjected to equilibrium conditions, remarkably decreased by around two-fold when sleep deprived. After recovery by sleep rebound, chromosome dynamics in these larvae increased by two-fold, reaching the levels observed during nighttime sleep in the control larvae. This suggests that sleep raises chromosome dynamics in a homeostatic-dependent manner (Zada et al., 2019). To validate these findings, larvae were treated during daytime with melatonin, which is a hormone that promotes sleep, and it was found that their chromosome dynamics increased (Zada et al., 2019). This again supported the proposition that sleep increases chromosome dynamics. To establish that sleep is necessary in order to enhance chromosome dynamics, two groups of zebrafish, with (aanat2+/+) or without (aanat2-/-) melatonin signaling, were bred. As aanat2-/- larvae lack melatonin, they were expected to sleep less during nighttime even though they have an intact intrinsic molecular circadian clock. The results showed that the aanat2-/- larvae have greater reduction in chromosome dynamics compared to aanat2+/+ larvae (Zada et al., 2019). Therefore, the chromosome dynamics were similar in both the day and night, even though the molecular circadian clock is intact. This indicates that chromosome dynamics in neurons is regulated by sleep behaviour (Zada et al., 2019). 

Chromosome/Chromatin Dynamics and DNA Repair 

To establish the causal relationship between chromosome dynamics and reduction in DNA damage, some zebrafish were genetically modified to overexpress Lamina-associated polypeptide 2 (Lap2β), which is a protein that interacts with lamins and anchors chromatin to the nuclear lamina and inhibits chromosome dynamics when overexpressed. The number of γH2AX foci, which are a molecular marker of DNA damage, was measured in Lap2β-overexpressing neurons and control neurons respectively and was found to remarkably increase by 120% in Lap2β-overexpressing neurons in comparison with the control neurons during night-time (Zada et al., 2019). This indicates that the amount of DNA damage would increase when chromosome dynamics is inhibited. These results established that the chromosome dynamics induced by sleep is essential to cut DNA damage. 

One of the forms of DNA damage, double-strand breaks (DSBs), which is the most deleterious form, can be repaired in eukaryotic organisms by two major mechanisms: non-homologous end-joining (NHEJ) and homologous recombination (HR). In NHEJ, the more preferred pathway in mammalian cells, two broken ends can be directly ligated together and this can occur at any point of the cell cycle. However, HR only occurs primarily in the S/G2 phase and it works by using the unbroken homologous sister chromatid DNA sequence as a template to replicate information that was lost.

The basis of chromatin architecture and dynamics in DNA repair targeting DSBs has been considerably studied. In mammalian cells, chromatin mobility was found to be increased upon DNA damage. It has been proposed that the accessibility of DNA within a heterochromatin could be changed during DNA damage response. Studies have shown that DNA damage causes heterochromatin to unfold (Hauer and Gasser, 2017). For example, in human fibroblasts, chromatin relaxes in response to DNA damage and heterochromatin loss (Hauer and Gasser, 2017). An experiment of treatment with tert-butyl hydroperoxide (TBH), which is an agent that is responsible for the signalling of oxidative damage, showed that there was a change in the compaction of heterochromatin. It is therefore evident that chromatin dynamics are important in the process of DNA repair.

When DNA is damaged, depending on the nature of DNA injury and the phase of the cell cycle the cell is in when the damage was noticed, cells would respond by initiating a signal transduction cascade and induce cell cycle arrest at the G1/S transition, within the S phase or at G2/M transition. When there are too many DNA injuries that go unrepaired, the cell will induce programmed cell death (apoptosis) to protect the organism from being harmed by its possibly harmful self. 

However, under special circumstances, when DNA repair is erroneous or leads to blockage of transcription, this may produce mutations conferring selective advantage of clonal expansion and reduced gene expression – leading to serious consequences like cancer or aging (Bernstein et al., 2013). 

Conclusion

Many experts in sleep health advocate for greater support for night shift workers, such as the provision of greater opportunities for regular screenings of chronic diseases related to sleep deprivation or shift work. As for my dear schoolmates who may find themselves sleep-deprived, perhaps the time has come to seriously weigh whether the risks are worth binge-watching your favourite Netflix show!

References:

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Davis, S. and Mirick, D.K. (2006). Circadian Disruption, Shift Work and the Risk of Cancer: A Summary of the Evidence and Studies in Seattle. Cancer Causes & Control, 17(4), pp.539–545. 

Wendeu-Foyet, M.G., Bayon, V., Cénée, S., Trétarre, B., Rébillard, X., Cancel-Tassin, G., Cussenot, O., Lamy, P.-J., Faraut, B., Khedher, S.B., Léger, D. and Menegaux, F. (2018). Night work and prostate cancer risk: results from the EPICAP Study. Occupational and Environmental Medicine, [online] 75(8), pp.573–581. Available at: https://oem.bmj.com/content/75/8/573 [Accessed 21 Mar. 2021]. 

Cheung, V., Yuen, V.M., Wong, G.T.C. and Choi, S.W. (2018). The effect of sleep deprivation and disruption on DNA damage and health of doctors. Anaesthesia, 74(4), pp.434–440.

Vgontzas, A.N., Zoumakis, M., Bixler, E.O., Lin, H.-M., Prolo, P., Vela-Bueno, A., Kales, A. and Chrousos, G.P. (2003). Impaired nighttime sleep in healthy old versus young adults is associated with elevated plasma interleukin-6 and cortisol levels: physiologic and therapeutic implications. The Journal of clinical endocrinology and metabolism, [online] 88(5), pp.2087–95. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12727959 [Accessed 1 Dec. 2019].

Bernstein, C., R., A., Nfonsam, V. and Bernstei, H. (2013). DNA Damage, DNA Repair and Cancer. New Research Directions in DNA Repair. [online] Available at: https://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer.

Hauer, M.H. and Gasser, S.M. (2017). Chromatin and nucleosome dynamics in DNA damage and repair. Genes & Development, [online] 31(22), pp.2204–2221. Available at: http://genesdev.cshlp.org/content/31/22/2204.full#sec-6 [Accessed 22 Mar. 2021].

Miné-Hattab, J. and Darzacq, X. (2020). Chromatin Dynamics upon DNA Damage. Chromatin and Epigenetics. [online] Available at: https://www.intechopen.com/books/chromatin-and-epigenetics/chromatin-dynamics-upon-dna-damage [Accessed 22 Mar. 2021].

Zada, D., Bronshtein, I., Lerer-Goldshtein, T., Garini, Y. and Appelbaum, L. (2019). Sleep increases chromosome dynamics to enable reduction of accumulating DNA damage in single neurons. Nature Communications, [online] 10(1). Available at: https://www.nature.com/articles/s41467-019-08806-w.

Cirelli, C., Faraguna, U. and Tononi, G. (2006). Changes in brain gene expression after long-term sleep deprivation. Journal of Neurochemistry, [online] 98(5), pp.1632–1645. Available at: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1471-4159.2006.04058.x [Accessed 27 Apr. 2019].

da Costa Souza, A. and Ribeiro, S. (2015). Sleep deprivation and gene expression. Current Topics in Behavioral Neurosciences, [online] 25, pp.65–90. Available at: https://pubmed.ncbi.nlm.nih.gov/25646722/ [Accessed 21 Mar. 2021].

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