Epigenetics of physical exercise

Epigenetics of physical exercise is the study of epigenetic modifications resulting from physical exercise to the genome of cells. Epigenetic modifications are heritable alterations that are not due to changes in the sequence of nucleotides. Epigenetic modifications, such as histone modifications and DNA methylation, alter the accessibility to DNA and change chromatin structure, thereby regulating patterns of gene expression. Methylated histones can act as binding sites for certain transcription factors due to their bromodomains and chromodomains. Methylated histones can also prevent the binding of transcription factors by hiding the transcription factor's recognition site, which is usually found on the major groove of DNA. The methyl groups bound to the cytosine residues lie in the major groove of DNA, the same region most transcription factors use to read a DNA sequence. A common epigenetic tag found in DNA is the covalent attachment of a methyl group to the C5 position of the cytosine found in CpG dinucleotide sequences. CpG methylation is an important mechanism of transcriptional silencing. Methylation of CpG islands is shown to reduce gene expression by the formation of tightly condensed heterochromatin that is transcriptionally inactive. CpG sites in a gene are most commonly found in the promoter regions of a gene while also being present in non promoter regions. The CpG sites in non promoter regions tend to be constitutively methylated, causing transcription machinery to ignore them as possible promoters. The CpG site near promoter regions are mostly left unmethylated until a cell decides to methylate them and repress transcription. Methylation of CpGs in promoter regions result in the transcriptional silencing of a gene. Environmental factors including physical exercise have been shown to have a beneficial influence on epigenetic modifications.
Effects on cancer.
Physical exercise leads to epigenetic modifications that can have beneficial effects in cancer patients. The effect of physical exercise on DNA methylation patterns leads to increased expression of genes associated with tumor suppression and decreased expression of oncogenes. Cancer cells have non-normal patterns of DNA methylation including hypermethylation in promoter regions for tumor-suppressing genes and hypomethylation in promoter regions of oncogenes. These epigenetic mutations in cancer cells cause the cell to grow and divide uncontrollably, resulting in tumorigenesis. Physical exercise has been shown to reduce and even reverse these epigenetic mutations, increasing expression levels of tumor-suppressing genes and decreasing expression levels of oncogenes.
Hypermethylation in the promoter regions of tumor suppressor genes is thought to help cause some forms of cancer. The hypermethylation in the promoter regions of the tumor suppressing genes APC and RASSF1A are common epigenetic markers for cancer. The APC gene functions to make sure cells divide properly and maintain a correct number of chromosomes after division has completed. The RASSF1A gene product interacts with the DNA repair protein XPA. Physical exercise has been shown to decrease and even reverse these promoter hypermethylation, lowering the risk of the development of cancer. Decreased hypermethylation patterns reveal a transcriptionally accessible promoter region, allowing for increased expression of the tumor suppressing genes.
Physical exercise increases levels of eustress, or good stress, on the body. This eustress stimulates epigenetic modifications affecting the DNA genome of cancer cells. Environmental conditions, such as eustress, strongly induces expression of the tumor suppressor TP53 gene by influencing epigenetic modifications to be made to the cancer cells genome. The TP53 gene codes for the p53 protein, a protein important in the apoptotic pathway of programmed cell death. The p53 protein is important for the regulation of cell growth and apoptosis, so hypermethylation of the TP53 promoter region are common markers associated with the development of cancer. Other than methylation patterns affecting expression of TP53, microRNAs and antisense RNAs control the levels of the p53 protein by regulating expression of the p53 coding TP53 gene.
Breast cancer.
In a study on the epigenetic effects of physical exercise on breast cancer in women, blood samples from breast cancer patients were collected before and after 6 months of moderate-intensity aerobic exercise. The test group experienced 129 minutes of exercise on average per week compared to the control group’s 21.8 minutes a week. The study found 43 genes having significant changes in DNA methylation. Of the 43 genes, 3 of the genes experiencing reduced methylation levels were directly correlated with increased survival of breast cancer. The gene L3MBTL1, a known tumor suppressor, had methylation levels decreased by 1.48% in the exercise group while the limited exercise control group experienced a 2.15% increase in methylation. The 1.48% decrease in methylation of L3MBTL1 resulted in greater expression of the tumor suppressor while the 2.15% increase in methylation experienced by the limited exercise control group led to a decrease in expression. The findings of the study showed patients who exercised regularly had lower methylation levels and higher gene expression of L3MBTL1. These patients also experienced a greater than 60% reduction in risk of breast cancer death compared to patients in the limited exercise group.
Effects on aging.
DNA methylation.
Epigenetic mechanisms affected by physical exercise have also been seen to be involved in age-related processes. A major component of aging is significant loss of DNA methylation over time. Methyl deoxycytidine, which is a methylated cytosine on the 5’ carbon of a cytosine, is involved in the process of cell differentiation and maintenance. Cell differentiation involves methylation of different areas within the DNA of a cell, which can alter the transcription of genes. During cell differentiation, DNA methylation is important for establishing the identity and function of a cell because of its role in controlling gene expression. A recent study looking at genome DNA methylation of newborn infants and humans aged 100 years or older found that the older individuals had significantly decreased overall DNA methylation. As one ages, the amount of DNA methylation slowly begins to decrease.
Studies have also looked at methyl deoxycytidine residues from tissues collected from rodents at various ages. These studies found that DNA methylation loss increased significantly as the rodent aged. Thus, aging is related to a significant loss in DNA methylation. However, this loss of DNA methylation appears to be slowed by physical exercise under rare conditions, in generel this effect is not very well studied and so far it seems like there is no connection between DNA methylation and physical activity. Further studies have looked at the effects of physical exercise on DNA methylation and aging in humans. 
Another component of aging is the gradual shortening of telomeres located at the end of chromosomes. Telomeres are repetitive sequences located at the end of chromosomes whose purpose are to slow the process of shortening and cell damage which occurs after every cell division as well as stabilize the ends of DNA. Aging and age-related diseases are associated with the significant shortening of these sequences. The shrinking of telomeres occurs in somatic cells where telomerase, the enzyme in control of telomere lengthening, is not expressed.
However, it has been seen that telomeres can transcribe non-coding RNA, or functional RNAs that do not get translated into protein. Research has demonstrated that some of the non-coding RNAs transcribed at telomeres are involved in heterochromatin formation and stability of the telomeres. These non-coding RNAs can be positively impacted by physical exercise. Notably, a study found that mice exposed to short-term running phases had increased non-coding RNA transcription at telomeres as compared to sedentary controls. This increase in non-coding RNA transcription aided telomere stability, making the exercise group's telomeres less likely to be as affected by aging over time. Through helping to increase telomere stability, physical exercise can have positive impacts on aging by helping to decreasing the shortening of telomeres.
Effects on metabolic processes.
In addition to restructuring the muscular and skeletal system to better handle mechanical stress, physical exercise also affects gene expression with respect to metabolism. The effects are widespread and can affect anything from muscle growth to aerobic stamina to diabetes and other metabolic disorders.
In general, even a small amount of exercise can induce hypomethylation of the whole genome within muscle cells. This means that many regulatory genes can be turned on for pathways like muscle repair and growth. The intensity of the exercise directly correlates to the amount of promoter demethylation, so more strenuous exercise activates more genes.
MicroRNAs (miRNAs) interfere with mRNA that is present and render it unusable and therefore decrease the product of that mRNA. MiRNAs regulate many physiological processes, such as inflammation, angiogenesis (the creation of blood vessels), as well as ischemia (the restriction of blood flow within the vessels) prevention. Aerobic exercise reduces the overall number of various miRNAs within the skeletal muscle that produce negative effects. Stimuli that cause the body to enter an anabolic, or constructive, phase, such as resistance training as well as the correct diet, has also shown a reduction of miRNAs. This reduction may actually play a role in the growth of the muscle cell.
Class IIa Histone deacetyltransferases (HDACs) are highly expressed within human skeletal muscles. Exercise helps to reduce their activity, especially at promoters, which affects gene expression. In mice, this regulation of HDAC5 has been shown to increase the amount of type I fibers in muscle. Type I fibers are slow twitch, endurance fibers. This data agrees with human data that says the amount of type I fibers is positively correlated with the maximal aerobic capacity.
It also suggested that the amount of type 1 fibers is correlated with a histone acetyltransferase (HAT) that is involved in osteoblast differentiation and bone formation.
Diabetes.
Individuals with type II diabetes have hypermethylation of several genes within the muscle, like peroxisome proliferator-activated receptor gamma (PPAR-γ) and coactivator 1 alpha (PGC-1α). The hypermethylation of these genes decreases the expression of both mitochondrial DNA as well as PGC-1α mRNA. Exercise is a way to prevent and treat these effects by helping to hypomethylate PPAR-γ and PGC-1α. Additionally, exercise also increases expression of glucose transporter type 4 (GLUT4), which will also help with diabetes symptoms.
Effects on cognition.
Physical exercise causes four types of epigenetic alterations that affect cognition. An extensive 2017 review describes effects of exercise on the brain due to (1) DNA methylation, (2) histone acetylation, (3) histone methylation and (4) microRNA expression, and the consequences of these alterations on learning and memory (cognition).
DNA methylation.
As summarized in the 2017 review, in rats, exercise enhances the expression of the gene "Bdnf", which has an essential role in memory formation. Enhanced expression of "Bdnf" occurs through demethylation of its CpG island promoter at exon IV. Demethylation is implemented in part through the actions of thymine-DNA glycosylase and the base excision repair system.
Exercise decreases hippocampus expression of the gene-repressive DNA methylating enzymes DNMT1, DNMT3a and DNMT3b. The hippocampus has important functions in memory, spatial navigation and is part of the reward system. Exercise also attenuates the global methylation changes induced by stress.
Histone H3 acetylation.
Exercise causes acetylation of histone H3 in the exon IV promoter region of the "Bdnf" gene essential for memory formation. This acetylation contributes to upregulation of "Bdnf" in the brain hippocampi of rats. Two weeks of treadmill exercise improves memory performance in an inhibitory avoidance task.
Histone H3 methylation.
Histone methylation can cause transcription repression. Lysine can undergo mono-, di- and tri-methylation. Di- and tri-methylation of histone H3 at lysine 9 (H3K9) is related to transcription repression. Mice deficient in a particular histone-methyltransferase gene, KMT2A (also known as MLL1), in adult excitatory neurons show impairments in hippocampus-dependent memory tasks. Aging induces decreases in the global methylation of H3K9 in the hippocampus. However, physical exercise counteracts the aging induced decreases in the global methylation of H3K9.
microRNA.
Eukaryotic cells can communicate directly with each other through cell–cell contact or at distance by secreting soluble factors such as hormones, growth factors, cytokines and chemokines. Both RNA and microRNAs (miRNAs) can be functionally transferred from a donor to a recipient cell via membrane-derived vesicles called exosomes. Similarly to hormones, miRNAs are released into the circulation (called circulating miRNAs or c-miRNAs), to affect cells throughout the organism. The c-miRNAs are transported by exosomes, high-/low-density lipoproteins, apoptotic bodies, and RNA-binding proteins. A bout of exercise increases c-miR-223 levels in the circulation in young healthy men, while lack of miR-223 leads to hippocampal-dependent memory deficits and neuronal cell death.
With further knowledge of epigenetic pathways, exercise will continue to show its benefits in all phases of life including but not limited to cancer prevention and treatment, aging, metabolism and metabolic disorders like diabetes and cognition.