Aastha Dharia ’20 and Danny Kim ’21


How Sleep Deprivation Influences the Epigenome

Imagine that you are a college student, whose professors all magically decided to give exams and projects due on the same date. For some reason, you procrastinated until the last minute, and now you need to pull an all-nighter at the library. You begrudgingly head to the fourth floor of the library, prepared to stay awake with a bag full of your favorite candy bars and snacks, a Venti Starbucks iced coffee, and a couple cans of Red Bull. You finally leave the library with sleepy eyes just as the sun slowly rises above the horizon. On the actual exam, you feel very tired and have trouble concentrating. A couple days later, you get your not-so-great grade back for your exams and projects, and you make a promise to yourself that you will never make the same mistake. But two weeks later, you end up doing it again a couple weeks later. This all sounds too familiar, right?

Well, just like in this hypothetical situation, if you have ever pulled an all-nighter in high school or college, or just had a restless night, you have probably also noticed how foggy your brain feels the next day. Even after that cup of joe or Red Bull, everything feels a little bit slower, a little bit harder to understand and remember. As you take notes in class, something just seems off, and it does not feel like you are truly processing anything that is coming out of your professor’s mouth or the hot gossip your friend is sharing next to you. This is not all in your head. In fact, your actual brain is not processing quite as quickly or making nearly as many connections on a cellular level.

Sleep is an integral part of daily functioning for everyone. The reason why you feel so sluggish after an all-nighter is because sleep deprivation disrupts cognitive functions, including learning and memory, and has a profound impact on the molecular biology of the brain. This is especially true of the epigenome, which encompasses all of the proteins and other factors connected to your DNA that help control which genes are turned on and off. What makes the epigenome so special is that it is regulated by external factors (such as how much sleep you have had) and is able to affect gene expression without actually changing the sequence of your DNA. 

To truly be able to understand the mind boggling world of neuroepigenetics and how sleep, or lack thereof, impacts the epigenome, one first has to understand the basics of gene expression and what epigenetics actually is. Consider the quizzes you used to take in magazines where the answer to every question led to a new set of questions based on your answer until you reached a final outcome. They were like a map where each decision had an impact on the next leg of your journey. The same idea can be used to understand epigenetics. Each decision you make about your external environment can have an impact on the internal mechanisms in your body. If DNA is the instructional manual to build genes, and genes help regulate important decisions in your body, then your decisions about what you do to your body serve as the toggle to the switch that determines which processes are turned on and which processes are turned off.

In both human and animal models, the relationship between sleep deprivation and the epigenome has been widely studied. In part, the importance of the neuroepigenome – the epigenome of the brain and the nervous system – is highlighted by evidence linking it to changes in the physiology of the brain. The epigenome plays a critical role in regulating gene expression responsible for memory storage and synaptic plasticity, both of which determine the brain’s capacity for adapting to experiences. This role is further backed by the synaptic homeostasis hypothesis, which explains our innate need for sleep in order to maintain healthy neuronal connections and prevent our brains from descending into a general state of chaos. The hippocampus, which is the portion of the brain responsible for memory and learning, is shown to be especially sensitive to sleep loss. Changes in behavior observed from experiments involving sleep and the hippocampus are a result of genetic and physiological changes, further cementing the involvement of neuroepigenetic mechanisms. Sleep loss has also been shown to disrupt metabolic and hormonal regulation and increase the risk of obesity, and this link between sleep and brain integrity and activity can be seen with a variety of brain imaging technologies. 

When it comes to sleep, how much sleep you are getting may be impacted by a number of factors such as your work, your lifestyle, stimulants you may be taking, and other health conditions. Whatever the reason, if you are not receiving enough sleep, the deprivation can result in a number of internal changes within the gene that can impact your ability to function.

Mechanistic Changes

As you go through your quiz, the answers you provide about your sleeping habits can toggle three different kinds of switches in your epigenome: (1) DNA methylation, (2) histone modification, and (3) non-coding RNA molecules. These mechanisms can function on their own to change gene expression, or in some cases may work together to cause changes in phenotypic expression – in other words, the changes in behavior or physiology you may be experiencing.

Gaine, M. E., Chatterjee, S., & Abel, T. (2018). Sleep deprivation and the epigenome. Frontiers in Neural Circuits, 12, 14. https://doi.org/10.3389/fncir.2018.00014

Figure 1. The Influence of Sleep on Gene Expression

Gaine, M. E., Chatterjee, S., & Abel, T. (2018). Sleep deprivation and the epigenome. Frontiers in Neural Circuits, 12, 14. https://doi.org/10.3389/fncir.2018.00014

DNA Methylation

The most common change that occurs is DNA methylation. This toggle switch works by  enabling addition of a small molecular tag known as a methyl group (-CH3) to the nucleotides that make up DNA. It is most often added to a dinucleotide sequence composed of a cytosine and a guanine connected by a phosphate (termed CpG). While the brain needs a certain number of these tags to function properly, when you do not get enough sleep, your body often starts to attach too many of these tags to the CpG complexes within your genes resulting in a process called hypermethylation. A class of molecules used to regulate DNA methylation called DNA methyltransferases (DNMTs) starts overexpressing, which in turn functions to reduce gene expression by calling upon a repressor molecule known as methyl-CpG binding protein 2 (MeCP2) to stop the gene from transcribing molecules important for essential functioning. Because many of these molecules are necessary for brain function, studies show that disrupting the normal level of DNA methylation through lack of sleep can impair neurological function as well as biological.

Histone Modification

Another common epigenetic change that acts as a toggle switch is histone modification. Histones are proteins that help package DNA into a more compact form. How tightly DNA wraps around the histones changes how much DNA is available to be expressed and therefore controls the degree of gene expression. The relationship functions much like a spool of thread — how tightly the thread is wrapped around the spool determines how much thread is available for use. Adding or removing chemical tags affects how tightly DNA wraps around them. One of these common tags is an entails attaching an acetyl group to the histones, allowing more access to the DNA through a process termed histone acetylation. Although the study of other histone modifications associated with sleep is still in its infancy, the relationship between histone acetylation and sleep has been studied relatively extensively. 

Histone acetylation is very crucial in gene expression. One of the main enzymes responsible for the action are called histone acetyltransferases (HATs), which as the name suggests, transfer acetyl groups to histones. On the other hand, the enzymes that remove the acetyl groups are histone deacetylases (HDACs).

One of these histone acetyltransferases (HAT) is a gene called CLOCK. You’ve probably heard about the circadian rhythm, which typically refers to the internal biological clock that controls our sleep cycle, and CLOCK is one of the specific genes that regulates this biological cycle. CLOCK performs this role by either increasing or decreasing expression of other genes involved in the circadian rhythm. Sleep deprivation leads to errors in the CLOCK activity, which can further disrupt sleep homeostasis and the circadian rhythm.

Another major way that sleep loss can cause problems is through the hippocampus. Recall that the hippocampus is responsible for learning and memory. The hippocampus is ultrasensitive to sleep deprivation, which can cause spatial memory loss. Specifically, lack of sleep lowers the levels of a specific histone acetyltransferase, called CBP HAT, and the messenger RNA (mRNA) that becomes translated to protein for this enzyme. At the same time, the level of histone deacetylases removing acetyl groups increases and the net result is an overall decrease in histone acetylation. This decline leads to lower expression of the genes crucial for maintaining hippocampal integrity, including a specific nerve growth factor called the brain-derived neurotrophic factor (BDNF). When there is a decrease in expression of this factor, it disrupts a series of signals in the brain that results in cognitive deficits and memory impairment. Research has shown this effect can be reversed Trichostatin A, which is an HDAC inhibitor that prevents the removal of the acetyl tags, illustrating the significant role that histone acetylation plays in memory and learning in the hippocampus. 

Non-Coding RNAs

The last toggle switch controlled by your decisions about sleep is non-coding RNAs, which as the name suggests, do not become translated to proteins. Non-coding RNAs play many important functional and regulatory roles, so it is of no surprise that non-coding RNAs also play a significant role in how sleep can affect cognitive functions. In the context of sleep, the two types of non-coding RNAs of interest are long non-coding RNAs (lncRNAs) and microRNAs. As the prefixes suggest, the difference is in the length of the nucleotides that make up the RNA sequences. Long non-coding RNAs are on average 200 nucleotides long, while microRNAs are about 22 nucleotides long. Much like histones, lncRNAs are also closely linked to the circadian rhythm. Research has shown that removing lncRNAs in mice brains causes dysregulation of CLOCK and other circadian rhythm-related genes, and sleep deprivation has been correlated with differential expression of several lncRNAs in mice brains. 

MicroRNAs are also able to regulate gene expression by binding to mRNAs. This binding results in subsequent degradation of the mRNA, thereby hindering gene expression. Many studies have shown that some microRNAs repress the expression of circadian rhythm genes, and the levels of these microRNAs have been shown to increase after sleep loss in rats. In the human brain, microRNAs are expressed differentially in specific brain regions depending on sleep periods, suggesting that sleep may regulate tissue-specific microRNA expression. Most importantly, microRNAs have been shown to play a direct role in inhibiting overall mRNA translation in the hippocampus.

Why do your brain and your body care?

Through a number of studies, it has become pretty clear that sleep deprivation has a significant impact on brain plasticity, as well as cognitive and metabolic function and may even play a role in some psychiatric diseases. In various mice studies on sleep wave patterns, DNA methylation has been found to have an impact on the genes and gene pathways involved in signaling, neurotransmission, and synaptic plasticity. Through electroencephalography (EEG), a technique used to record electrical activity in the brain, we also know that regulation of sleep activity is tied to synaptic downscaling, a method used by your brain to maintain plasticity and improve cognitive performance and learning.

Much research on histone modifications further links changes in the histone code from sleep disturbances to differential abilities in learning and memory, a and can link sleep disturbances to neurodegenerative and neuropsychiatric disorders. How healthy your brain is will also correlate with your mood, which may have a cyclic effect on how well an individual is able to handle specific psychiatric conditions. Finally, we know that lack of sleep can reduce your metabolic function, which leads to higher risk of obesity, as well as further complications such as heart disease, strokes, and abnormally high blood pressure.

There is still a lot of research to be done to determine how exactly sleep interacts with the brain and the implications of it, but this is certainly a start. From what we know, we have already started identifying how to combat sleep deprivation through stimulants such as caffeine and modafinil, which both help correct for the negative effects of sleep deprivation by targeting neurotransmitters in the brain such as dopamine and adenosine. However, we have only just begun to uncover the mechanisms involved, and further research could go a long way in helping identify how the link between sleep and epigenetics impacts the brain, the body, and the associated disorders and interventions that go along with them.

Now you fully understand what we mean when we say that your epigenome needs sleep, too. Sleep is an integral part of daily function and normal physiological processes because of how much of a role it plays in regulation and expression of genes involved in many important brain functions. Next time you have a lot on your plate, try to spread out your work so that you can get some sleep. Not only your body and grade, but also your epigenome will thank you. Get some sleep tonight!

References

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