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[[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 [[nucleotide]]s.[9] Epigenetic modifications, such as [[histone]] modifications and [[DNA methylation]], alter the accessibility to DNA and change [[chromatin]] structure, thereby regulating patterns of [[gene expression]].[9] 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. [9] CpG methylation is an important mechanism of [[Gene silencing|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 (genetics)|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.
[[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 [[nucleotide]]s.<ref name="Handy"/> Epigenetic modifications, such as [[histone]] modifications and [[DNA methylation]], alter the accessibility to DNA and change [[chromatin]] structure, thereby regulating patterns of [[gene expression]].<ref name="Handy">{{cite journal|last=Handy|first=D. E.|coauthors=Castro, R., & Loscalzo, J.|year=2011|title=Genetics Primer for the General Cardiologist|journal=Circulation|volume=123|issue=467|pages=2145–2156}}</ref> 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.<ref name="Handy"/> CpG methylation is an important mechanism of [[Gene silencing|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 (genetics)|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.


== Epigenetics of Physical Exercise and 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.[9] 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.
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.<ref name="Handy"/> 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.[1] 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.[1] Decreased hypermethylation patterns reveal a transcriptionally accessible promoter region, allowing for increased expression of the tumor suppressing genes.
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.<ref name="Coyle">{{cite journal|last=Coyle|first=YM|coauthors=Xie XJ, Lewis CM, Bu D, Milchgrub S, Euhus DM|date=February 2007|title=Role of physical activity in modulating breast cancer risk as defined by APC and RASSF1A promoter hypermethylation in nonmalignant breast tissue|journal=Cancer Epidemiol Biomarkers Prev|volume=16|issue=2|pages=192–196|doi=10.1158/1055-9965.EPI-06-070|pmid=17301249}}</ref> 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.<ref name="Coyle"/> 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.[4] 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.[4] 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, [[Micro RNA|microRNAs]] and antisense RNAs control the levels of the p53 protein by regulating expression of the p53 coding TP53 gene.[4]
Physical exercise increases levels of eustress, or good stress, on the body. This eustress stimulates epigenetic modifications affecting the DNA genome of cancer cells. <ref name="Sanchis-Gomar">{{cite journal|last=Sanchis-Gomar|first=F.|coauthors=Garcia-Gimenez, J. L., Perez-Quilis, C., Gomez-Cabrera, M. C., Pallardo, F. V., & Lippi, G.|date=December 2012|title=Physical exercise as an epigenetic modulator: Eustress, the "positive stress" as an effector of gene expression|journal=J Strength Cond Res|volume=26|issue=12|pages=3469–72|doi=10.1519/JSC.0b013e31825bb594|pmid=22561977}}</ref>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.<ref name="Sanchis-Gomar"/> 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, [[Micro RNA|microRNAs]] and antisense RNAs control the levels of the p53 protein by regulating expression of the p53 coding TP53 gene.<ref name="Sanchis-Gomar"/>


=== Breast 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.[3] 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.[3] 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.[3] These patients also experienced a greater than 60% reduction in risk of breast cancer death compared to patients in the limited exercise group.[3]
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.<ref name="Zeng">{{cite journal|last=Zeng|first=H.|coauthors=rwin, M. L., Lu, L., Risch, H., Mayne, S., Mu, L., et al.|date=May 2012|title=Physical activity and breast cancer survival: an epigenetic link through reduced methylation of a tumor suppressor gene: L3MBTL1|journal=Breast Cancer Res Treat|volume=133|issue=1|pages=127–35|doi=10.1007/s10549-011-1716-7|pmid=21837478}}</ref> 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.<ref name="Zeng"/> 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.<ref name="Zeng"/> These patients also experienced a greater than 60% reduction in risk of breast cancer death compared to patients in the limited exercise group.<ref name="Zeng"/>


== Epigenetics of Physical Exercise and Aging ==
== Epigenetics of Physical Exercise and Aging ==


=== DNA Methylation ===
=== 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 [5]. Methyl deoxycytidine, which is a methylated [[cytosine]] on the 5’ carbon of a cytosine, is involved in the process of [[Cellular differentiation|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 [14]. As one ages, the amount of DNA methylation slowly begins to decrease.
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.<ref name="Wilson">{{cite journal|last=Wilson|first=V. L.|coauthors=Smith R. A., Ma S., Cutler R.G.|date=July 25, 1987|title=Genomic 5-methyldeoxycytidine decreases with age|journal=J Biol Chem.|volume=262|issue=21|pages=9948–51|pmid=3611071}}</ref> Methyl deoxycytidine, which is a methylated [[cytosine]] on the 5’ carbon of a cytosine, is involved in the process of [[Cellular differentiation|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.<ref name="Heyn">{{cite journal|last=Heyn|first=H|coauthors=Li N, Ferreira HJ, Moran S, Pisano DG, Gomez A, Diez J, Sanchez-Mut JV, Setien F, Carmona FJ, et al.|date=June 26, 2012|title=Distinct DNA methylomes of newborns and centenarians|journal=Proc Natl Acad Sci U S A|volume=109|issue=26|pages=10522–7|doi=10.1073/pnas.1120658109|pmid=22689993}}</ref> 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 [5]. Thus, aging is related to a significant loss in DNA methylation [5,14]. 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 [12]. Thus, physical exercise can affect aging through slowing the rate of the loss of DNA methylation over time.
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.<ref name="Wilson"/> Thus, aging is related to a significant loss in DNA methylation.<ref name="Wilson"/><ref name="Heyn"/> 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.<ref name="Zhang">{{cite journal|last=Zhang|first=F. F.|coauthors=Cardarelli R, Carroll J, Zhang S, Fulda KG, Gonzalez K, Vishwanatha JK, Morabia A, Santella RM|date=Mar 2011|title=Physical activity and global genomic DNA methylation in a cancer-free population|journal=Epigenetics|volume=6|issue=3|pages=293–9|doi=10.4161/epi.6.3.14378|pmid=21178401}}</ref> Thus, physical exercise can affect aging through slowing the rate of the loss of DNA methylation over time.


=== Telomeres ===
=== Telomeres ===
Another component of aging is the gradual shortening of telomeres located at the end of chromosomes. [[Telomere]]s 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 [[Telomere#Shortening|shortening]] of these sequences. The shrinking of telomeres occurs in somatic cells where telomerase, the enzyme in control of telomere lengthening, is not expressed [13].
Another component of aging is the gradual shortening of telomeres located at the end of chromosomes. [[Telomere]]s 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 [[Telomere#Shortening|shortening]] of these sequences. The shrinking of telomeres occurs in somatic cells where telomerase, the enzyme in control of telomere lengthening, is not expressed.<ref name="Henriques">{{cite journal|last=Henriques|first=C. M.|coauthors=Ferreira, M. G.|title=Consequences of telomere shortening during lifespan|date=December 2012|journal=Curr Opin Cell Biol|volume=24|issue=6|pages=804–8|doi=10.1016/j.ceb.2012.09.007|pmid=23127607}}</ref>


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 [6,14]. 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 [7]. 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.
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.<ref name="Shoeftner">{{cite journal|last=Shoeftner|first=S.|coauthors=Blasco M. A.|date=April 2010|title=Chromatin regulation and non-coding RNAs at mammalian telomeres|journal=Semin Cell Dev Biol.|volume=21|issue=2|pages=186–93|doi=10.1016/j.semcdb.2009.09.015|pmid=19815087}}</ref><ref name="Heyn"/> 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.<ref name="Werner">{{cite journal|last=Werner|first=C.|coauthors=Hanhoun M., Widmann T., et al.|date=August 5, 2008|title=Effects of physical exercise on myocardial telomere-regulating proteins, survival pathways, and apoptosis|journal=J Am Coll Cardiol|volume=52|issue=6|pages=470–82|doi=10.1016/j.jacc.2008.04.034|pmid=18672169}}</ref> 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 ==
== 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 [11].
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.<ref name="Ntanasis-Stathopoulos">{{cite journal|last=Ntanasis-Stathopoulos|first=J.|coauthors=Tzanninis, J-G., Philippou, A., and Koutsilieris, M.|date=Jun 2013|title=Epigenetic regulation on gene expression induced by physical exercise|journal=J Musculoskelet Neuronal Interact|volume=13|issue=2|pages=133–46|pmid=23728100}}</ref>


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 [11].
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.<ref name="Ntanasis-Stathopoulos"/>


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 [11].
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.<ref name="Ntanasis-Stathopoulos"/>


Class IIa Histone deacetyltransferases ([[HDAC]]s) 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.
Class IIa Histone deacetyltransferases ([[HDAC]]s) 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 ([[Histone acetyltransferase|HAT]]) that is involved in [[osteoblast]] differentiation and bone formation [11].
It also suggested that the amount of type 1 fibers is correlated with a histone acetyltransferase ([[Histone acetyltransferase|HAT]]) that is involved in [[osteoblast]] differentiation and bone formation.<ref name="Ntanasis-Stathopoulos"/>


===Diabetes===
===Diabetes===


Individuals with [[Diabetes mellitus type 2|type II diabetes]] have hypermethylation of several genes within the muscle, like peroxisome proliferator-activated receptor gamma([[PPARγ|PPAR-γ]]) and coactivator 1 alpha([[PGC-1a|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|GLUT4]]), which will also help with diabetes symptoms [2,11].
Individuals with [[Diabetes mellitus type 2|type II diabetes]] have hypermethylation of several genes within the muscle, like peroxisome proliferator-activated receptor gamma([[PPARγ|PPAR-γ]]) and coactivator 1 alpha([[PGC-1a|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|GLUT4]]), which will also help with diabetes symptoms.<ref name="Ntanasis-Stathopoulos"/> <ref name="Ling">{{cite journal|last=Ling|first=C.|coauthors=Groop, L.|date=December 2009|title=Epigenetics: A Molecular Link Between Environmental Factors and Type 2 Diabetes|journal=Diabetes|volume=58|issue=12|pages=2|doi=10.2337/db09-1003|pmid=19940235}}</ref>


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.
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.


==References==
==References==
{{reflist}}
{{reflist|2}}


[[Category:Genetics]]
''The first version of this document was written as part of an epigenetics class at The University of Texas at Austin.''
[[Category:Epigenetics]]

1. Coyle YM, Xie XJ, Lewis CM, Bu D, Milchgrub S, Euhus DM (2007) Role of physical
activity in modulating breast cancer risk as defined by APC and RASSF1A promoter hypermethylation in
:nonmalignant breast tissue. Cancer Epidemiol Biomarkers Prev 16(2):192–196

2. Ling, C., and L. Groop. "Epigenetics: A Molecular Link Between Environmental Factors and Type 2 Diabetes.”
Diabetes 58.12 (2009): 2718-725.

3. Zeng, H., Irwin, M. L., Lu, L., Risch, H., Mayne, S., Mu, L., et al. (2012). Physical
activity and breast cancer survival: an epigenetic link through reduced methylation of a tumor suppressor gene
:L3MBTL1 . Breast Cancer Res Treat , 133, 127-135.

4. Sanchis-Gomar, F., Garcia-Gimenez, J. L., Perez-Quilis, C., Gomez-Cabrera, M. C., Pallardo, F. V., & Lippi,
G. (2012). PHYSICAL EXERCISE AS AN EPIGENETIC MODULATOR: EUSTRESS, THE
:“POSITIVE STRESS” AS AN EFFECTOR OF GENE EXPRESSION . The Journal of Strength and Conditioning Research , 26 (12), 3469-3472.

5. Wilson V. L., Smith R. A., Ma S., Cutler R.G. (1987). Genomic 5-methyldeoxycytidine decreases with age. The
Journal of biological chemistry. 262(21), 9948-9951

6. Shoeftner S., Blasco M. A. (2010). Chromatin regulation and non-coding RNAs at mammalian telomeres.
Seminars in cell and developmental biology . 21(2), 186-193.

7. Werner C., Hanhoun M., Widmann T., et al. (2008). Effects of physical exercise on myocardial
telomere-regulating proteins, survival pathways, and apoptosis. Journal of the American College of
:Cardiology, 52(6), 470-482.

8. Kaliman, P., Parrizas M., Lalanza J. F., et al. (2011). Neurophysiological and epigenetic effects of physical
exercise on the aging process. Ageing Research Reviews. 10(4), 475-486.

9. Handy, D. E., Castro, R., & Loscalzo, J. (2011). Genetics Primer for the General Cadriologist. Circulation, 123, 2145-2156.

10. Blackburn EH. Telomere states and cell fates. Nature. 2000;408(6808):53-6.

11. Ntanasis-Stathopoulos,J., Tzanninis, J-G., Philippou, A., and Koutsilieris, M. (2013). "Epigenetic Regulation on Gene Expression Induced by Physical Exercise." J Musculoskelet Neuronal Interact
:13(2): 133-46. Web. <http://www.ismni.org/jmni/pdf/52/02STATHOPOULOS.pdf>.

12. Zhang, F. F., Cardarelli, R., Carroll, J., Zhang, J., Fulda, K. G., Vishwanatha, J. K., . . . Santella, R. M. (2011). Physical activity and global genomic DNA methylation in a cancer-free population.
:Epigenetics, 6(3), 293-299.

13. Henriques, C. M., & Ferreira, M. G. (2012). Consequences of telomere shortening during lifespan. Current Opinion in Cell Biology, 24(6), 804-808.

14. Heyn H, Li N, Ferreira HJ, Moran S, Pisano DG, Gomez A, Diez J, Sanchez-Mut JV, Setien F, Carmona FJ, et al. Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci
:USA. 2012;109:10522–10527.

{{Uncategorized|date=May 2014}}

Revision as of 18:50, 6 June 2014

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.[1] Epigenetic modifications, such as histone modifications and DNA methylation, alter the accessibility to DNA and change chromatin structure, thereby regulating patterns of gene expression.[1] 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.[1] 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.

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.[1] 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.[2] 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.[2] 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. [3]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.[3] 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.[3]

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.[4] 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.[4] 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.[4] These patients also experienced a greater than 60% reduction in risk of breast cancer death compared to patients in the limited exercise group.[4]

Epigenetics of Physical Exercise and 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.[5] 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.[6] 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.[5] Thus, aging is related to a significant loss in DNA methylation.[5][6] 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.[7] 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.[8]

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.[9][6] 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.[10] 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.[11]

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.[11]

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.[11]

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.[11]

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.[11] [12]

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.

References

  1. ^ a b c d Handy, D. E. (2011). "Genetics Primer for the General Cardiologist". Circulation. 123 (467): 2145–2156. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  2. ^ a b Coyle, YM (February 2007). "Role of physical activity in modulating breast cancer risk as defined by APC and RASSF1A promoter hypermethylation in nonmalignant breast tissue". Cancer Epidemiol Biomarkers Prev. 16 (2): 192–196. doi:10.1158/1055-9965.EPI-06-070. PMID 17301249. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  3. ^ a b c Sanchis-Gomar, F. (December 2012). "Physical exercise as an epigenetic modulator: Eustress, the "positive stress" as an effector of gene expression". J Strength Cond Res. 26 (12): 3469–72. doi:10.1519/JSC.0b013e31825bb594. PMID 22561977. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  4. ^ a b c d Zeng, H. (May 2012). "Physical activity and breast cancer survival: an epigenetic link through reduced methylation of a tumor suppressor gene: L3MBTL1". Breast Cancer Res Treat. 133 (1): 127–35. doi:10.1007/s10549-011-1716-7. PMID 21837478. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  5. ^ a b c Wilson, V. L. (July 25, 1987). "Genomic 5-methyldeoxycytidine decreases with age". J Biol Chem. 262 (21): 9948–51. PMID 3611071. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ a b c Heyn, H (June 26, 2012). "Distinct DNA methylomes of newborns and centenarians". Proc Natl Acad Sci U S A. 109 (26): 10522–7. doi:10.1073/pnas.1120658109. PMID 22689993. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  7. ^ Zhang, F. F. (Mar 2011). "Physical activity and global genomic DNA methylation in a cancer-free population". Epigenetics. 6 (3): 293–9. doi:10.4161/epi.6.3.14378. PMID 21178401. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  8. ^ Henriques, C. M. (December 2012). "Consequences of telomere shortening during lifespan". Curr Opin Cell Biol. 24 (6): 804–8. doi:10.1016/j.ceb.2012.09.007. PMID 23127607. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  9. ^ Shoeftner, S. (April 2010). "Chromatin regulation and non-coding RNAs at mammalian telomeres". Semin Cell Dev Biol. 21 (2): 186–93. doi:10.1016/j.semcdb.2009.09.015. PMID 19815087. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  10. ^ Werner, C. (August 5, 2008). "Effects of physical exercise on myocardial telomere-regulating proteins, survival pathways, and apoptosis". J Am Coll Cardiol. 52 (6): 470–82. doi:10.1016/j.jacc.2008.04.034. PMID 18672169. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  11. ^ a b c d e Ntanasis-Stathopoulos, J. (Jun 2013). "Epigenetic regulation on gene expression induced by physical exercise". J Musculoskelet Neuronal Interact. 13 (2): 133–46. PMID 23728100. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  12. ^ Ling, C. (December 2009). "Epigenetics: A Molecular Link Between Environmental Factors and Type 2 Diabetes". Diabetes. 58 (12): 2. doi:10.2337/db09-1003. PMID 19940235. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
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