Epigenetics has many connections to our cellular processes. It regulates the expression of our genes, so it wouldn’t surprise us that epigenetics is involved in the regulation of our circadian rhythms as well. But what exactly are these circadian rhythms and how can they be involved in certain processes of health and disease?
What are circadian rhythms?
Circadian rhythms are biological processes which govern not only our sleep-wake cycle, but also a wide variety of physiological functions, such as hormone release, feeding habits and digestion, temperature, and other important bodily functions. Circadian rhythms respond primarily to light and darkness, so this means that they follow a 24-hour periodicity regardless of changes in the cellular environment.
Disturbances in the circadian system have a profound impact on health, and they have been linked to several pathologies, including obesity, sleep, and psychiatric disorders like depression, Alzheimer or bipolar disorder, cardiovascular disease, changes in cognitive function and memory formation, and even cancer.
Circadian clocks and epigenetics
Circadian or biological clocks are our innate timing device and are found in nearly every tissue and organ of the body.
Our inner clocks are controlled by an anatomical structure in the brain localized in the anterior hypothalamus called the suprachiasmatic nucleus (SCN). This ‘master clock’ receives signals from the environment and coordinates the oscillating activity of peripheral clocks, which are located in almost all tissues. (1)
There has been a lot of research in this field lately, which has led to the identification of several genes with circadian characteristics, the so-called clock-controlled genes (CCGs), such as Period (PER), Timeless (TIM), Clock (CLK), BMAL1, and Cryptochrome (CRY). CLOCK/BMAL1 and PERs/CRYs are classified as the positive and negative regulators of the clockwork, respectively. (2)
Furthermore, we know that natural factors within the body as well as environmental cues, like the daylight, stimulate a cascade of signaling pathways that lead to the activation of a transcriptional program involving clock-controlled genes. Other environmental factors include food, temperature, stress, drugs, and age. (3)(4)
Likewise, thanks to several experimental studies, scientists have concluded that epigenetic processes are important mediators and regulators of rhythmic gene expression as well. These epigenetic controls can be exerted through a variety of mechanisms, which include DNA methylation, histone modification (acetylation and deacetylation) and non-coding RNAs, and each one has their roles in regulating the expression of clock genes, and ultimately, circadian phenotypes. (5)
How does it link to disease?
So, for example, scientist found out that CLOCK has intrinsic histone acetyltransferase (HAT) activity and uses histone acetylation and deacetylation to regulate circadian rhythms which can be enhanced by its partner, BMAL1. (4)
On the other hand, HDAC (histone deacetylase) has a function opposite to that of HAT and is also an important regulator of circadian rhythms and memory formation as well as metabolism. It is one of the HDAC subtypes involved in repressing BMAL1 expression, thus affecting circadian rhythms and metabolism.(4)
Besides metabolism, a number of genetic mouse models and human clinical studies reveal that the human Clock gene is expressed in colorectal cancer, and it has also been involved in the proliferation of breast cancer cells. In addition to CLOCK, BMAL1 has also been reported to be involved in cancer.
The PER repressors of the circadian clock have also been linked to cancer. Recent studies also demonstrate that low levels of Per1 and Per2 gene expression are associated with poor prognosis in gastric cancer. (6)
Finally, it has been suggested that the circadian clock regulates mechanisms to protect the organism from oxidative stress. For example, recent observations reveal that the dimer CLOCK/BMAL1 controls the expression of the transcription factor NRF2 in the lung which, in turn, drives the circadian transcription of antioxidant genes. (7)
Little is known about DNA methylation in circadian regulation in humans, but one study showed that homocysteine level was linked to DNA methylation. Moreover, epigenetic inactivation of clock genes due to promoter DNA methylation has been reported in various cancer cells, suggesting that it also plays a key role in linking the clock to cancer.(2)
MicroRNAs (miRNAs), probably the most intensively studied class of non-coding RNAs (ncRNAs) so far, may contribute to the regulation of circadian rhythms and have strong potential in circadian clock regulation too.
More interestingly, studies have also shown that diet affects the epigenetic regulation of circadian function. In a study of Japanese macaques, a maternal high-fat diet in utero disrupted the regulation of gene expression and increased individual variations in fetal hepatic Npas2, one of the CGs. These changes of gene expression and histone modification were reversed by postnatal diet. Other epigenetic modification induced by early-life environmental effects due to exposure to different lengths of light per day changes the SCN and neuronal Per1 gene expression and behavior after birth in mice.
In sum, this is a new emerging research field and there’s still a lot to be investigated, but hopefully in the near future, we
can learn more about epigenetics of circadian systems, other links on
health and disease, and what can we do about it.
- Masri S, Sassone-Corsi P. (2013). The circadian clock: a framework linking metabolism,epigenetics and neuronal function. Nat Rev Neurosci. 2013 Jan;14(1):69-75.
- Chengwei Li, Changxia Gong, Shuang Yu, Jianguo Wu, and Xiaodong Li (2012), “Epigenetic Control of Circadian Clock Operation during Development,” Genetics Research International, 2012, Article ID 845429, 8 pages,
- Bellet, Marina Maria and Paolo Sassone-Corsi. (2010) “Mammalian circadian clock and metabolism – the epigenetic link” Journal of cell science vol. 123,Pt 22 (2010): 3837-48.
- Jürgen A. Ripperger, Martha Merrow (2011) “Perfect timing: Epigenetic regulation of the circadian clock”, FEBS Letters, 585, 10, 2011, 1406-1411.
- Masri, S., Kinouchi, K., & Sassone-Corsi, P. (2015). Circadian clocks, epigenetics, and cancer. Current opinion in oncology, 27(1), 50-6.
- Orozco-Solis, R., & Sassone-Corsi, P. (2014). Circadian clock: linking epigenetics to aging. Current opinion in genetics & development, 26, 66-72.