Epigenetics Pt. 2 | DNA Methylation

Written & Researched by Lilly Curtis


** Please read Pt. 1 first, which introduces epigenetics and discusses histone modification. **


Another modification of epigenetics is DNA methylation, when a chemical group is added onto a specific place on the DNA and blocks proteins from reading the gene. This chemical group can be removed through a process called demethylation, that turns genes ‘on,’ in comparison to methylation which turns genes ‘off.’ Newborns are found to have the highest DNA methylation, due to the formation of specific cells, while people over the age of 100 have the lowest. The age of twenty-six have a methylation in between the two. DNA methylation proves one of the strongest connections epigenetics have with external influences, since chemical groups can be changed depending on what an organism consumes. Smokers tend to have less DNA methylation than non-smokers, however, if a smoker quits for a couple years, DNA methylation can increase back to the levels of a non-smoker. Epigenetics is reversible, unlike the majority of genetic changes (1).


Single genes and groups of genes have been identified as specially methylated in cancers. A journal by Costa, Fabricio on epigenomics in cancer management reviews the current progress in diagnosing patients and identifying cancer early on through epigenetic tests (2). DNA methylation tests can be used as molecular biomarkers to assess a patient’s current condition with prognosis before diagnosis, while, “while histone modification can be used as markers to monitor patients and determine their treatment regimens.” Other molecular subtypes based on DNA methylation have been identified in many cancer types including gliomas, gastric cancer, and leukemia. The FDA has already approved some epigenetic drugs, such as against tumors, through DNA methylation inhibitors, histone modification inhibitors, and small molecules that target chromatin-remodeling proteins. Costa concludes,

“The identification of all epigenetic modifications implicated in gene expression is the next step for a better understanding of human biology in both normal and pathological states.”

The use of methylation levels and methylome chemicals in relation to distinct malignants has been found to be vitally useful in distinguishing heritable cancer. A peer reviewed source in 2003 says, “Some cancers have unique methylomes that define distinct molecular subtypes of cancer. (3)" The study focused specifically on colorectal cancer, in which a hypermethylator phenotype called the CpG island methylator phenotype (CIMP) was seen predominantly in the elderly and in the right colon. Colorectal cancers were also found to have increased methylation levels at the SEPT9 gene, giving rise to the production of methylation level testing. For example, the performance of the Septin9 DNA methylation based blood test with a fecal immunochemical test for CRC screening was tested in 2014, and found to have a sensitivity of 72%. It’s negative predictive values were 99.8% (4).


DNA methylation tests for breast cancer is also reinforced by a systematic review of published DNA methylation studies in blood-derived DNA of BC patients in comparison to healthy controls (5). Breast cancer is the most common malignancy in women worldwide. Currently, the prognosis of the disease is dependent on early detection, most commonly through mammography and specific gene mutation tests are only used for hereditary BC, which is around 5-10% of cases. However, a certain methylation level of the gene BRCA1 was correlated with BC risk stratification. Having a mutation in the BRCA1 gene turns the gene “off,” leading to a down regulation of immune response. The journal concludes,

“Our review suggests the possibility of using blood-based methylation markers for risk stratification or the early detection of BC, as a number of studies support an association between methylation changes in blood and BC risk.”

DNA methylation has also been found to change over time due to the “epigenetic aging” process. A peer reviewed source by Yu, Ming et al on epigenetic aging with regards to its implication in cancer revealed biological tissue aging and how the construction of various epigenetic modifications can predict human clinical outcomes and health/life span (6). For example, a long term study in Sweden and England showed pre-pubescent young men who ate unhealthy and smoked would go on to have generations that lived a shorter life expectancy (7). Epigenetic marks, specifically DNA methylation that introduces chemical compounds that turn off useful genes, have long term health effects on children dependent on the DNA sequence of the sperm. Yu, Ming et al describes, “The fact that the epigenetic state of the genome is plastic and modifiable, unlike the genetic state, suggests that the possibility of slowing or reversing this process is plausible. (8)” Therefore, environmental influences hold large implications for the changes made in epigenetics, giving humans the potential to reprogram their cells and the futures of their children.


Stay tuned for part 3 on environmental influences on DNA!



References

(1) “What is Epigenetics?” CDC. August 3, 2020.


(2) Costa, Fabricio F. “Epigenomics in cancer management.” Cancer management and research vol. 2 255-65. 27 Oct. 2010.


(3) Yamashita, Kentaro et al. “Genetics supersedes epigenetics in colon cancer phenotype.” Cancer cell vol. 4,2 (2003): 121-31.


(4) Johnson, David A et al. “Plasma Septin9 versus fecal immunochemical testing for colorectal cancer screening: a prospective multicenter study.” PloS one vol. 9,6 e98238. 5 Jun. 2014.


(5) Tang, Q., et al. Blood-based DNA methylation as biomarker for breast cancer: a systematic review. Clin Epigenet 8, 115 (2016).


(6) Yu, Ming et al. “Epigenetic Aging: More Than Just a Clock When It Comes to Cancer.” Cancer research vol. 80,3 (2020): 367-374.


(7) Vågerö, D., Pinger, P.R., Aronsson, V. et al. Paternal grandfather’s access to food predicts all-cause and cancer mortality in grandsons. Nat Commun 9, 5124 (2018).


(8) Yu, Ming et al. “Epigenetic Aging: More Than Just a Clock When It Comes to Cancer.” Cancer research vol. 80,3 (2020): 367-374.

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