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Topic of choice: 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. The result of these modifications includes the prevention of cognitive decline, mitochondrial damage, and reduced risk of cancer.

Epigenetics of physical exercise and 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.

A group of proteins called the sirtuins regulate the activity of other proteins involved in cell survival, duplication, and reduction of reactive oxygen species in the mitochondria. Physical exercise is shown to increase sirtuin expression. Because sirtuins control proteins involved in cell proliferation, growth, and the cell cycle, such as p53, they can be important in the prevention of cancer. The increase in sirtuin expression from physical activity ultimately reduces the risk and effects of cancer.

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.

Cognition
Many studies have been done to look at the effect of physical activity on aging and cognition. A recent study looked at genes expressed in the hippocampus of mice. They exposed a group of mice to physical activity, while having another group of sedentary mice. These hippocampal genes were associated with neuroplasticity, cell excitability, as well as other mental processes. The physical exercise treatment group showed reduced anxiety and cognitive improvement, which included improved memory and learning. . The epigenetic changes resulting from the exercise included histone acetylation, but also phosphorylation of certain amino acids. The study also found that offspring from exercised mothers had inherited the epigenetic changes, along with the cognitive improvement. Physical exercise also affects the expression of proteins involved in growth, capillary formation, and control of nerve cells. VEGF, IGF-1, and BDNF are some proteins that are effected by epigenetic modifications resulting from physical activity.

Muscular atrophy
Muscular atrophy, which is the loss of muscle mass, is an inevitable side effect of aging. The formation of muscle tissue, also known as myogenesis, involves regulatory factors such as MyoD, Myf5, and MRF4, which are all involved in muscle tissue formation. Physical exercise can cause epigenetic changes to these genes over time. The epigenetic modifications from physical activity to myogenesis genes are caused by post-translational modifications to histones. Physical activity results in histone modifications, and therefore expression of muscle growth genes changes. These changes help prevent and slowdown the muscular atrophy that results from aging, or a sedentary lifestyle.

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. Further studies have looked at the effects of physical exercise on DNA methylation and aging in humans. This found that genome wide DNA methylation in adult individuals who obtained thirty or more minutes of exercise a day had significantly more DNA methylation as compared to sedentary individuals. Thus, physical exercise can affect aging through slowing the rate of the loss of DNA methylation over time.

Telomeres
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.

Epigenetics of physical exercise and 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.

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.