DNA Methylation And Aging

Introduction

This report will discuss some general topics on DNA Methylation and its link with aging. First paragraph will talk about DNA Methylation in general, second paragraph will discuss DNA Methylation and its link to X-Chromosome inactivation, third paragraph will discuss DNA Methylation and its correlation with Cancer, and in the fourth paragraph will discuss DNA Methylation relationship to Aging.

Basic information about DNA Methylation

DNA methylation controls gene expression in organisms. Gene slicing through methylation happens by the activity of methyltransferases DNA methylation patterns that are established by the de novo DNA methyltransferases (DNMTs) DNMT3A and DNMT3B and are subsequently maintained by DNMT1. [1]

Silencing pathway

There are many different routes to gene silencing by methylation, the most direct one involved is by interfering with transcription factors or basal transcriptional mechanisms that interact with cytosines in the major groove of double helices. Transcription factors ,that an extensive amount of mammals posses DNA recognition elements containing CpG-rich. DNA methylation can eliminate their ability to act in many important regulatory sites. transcriptional mechanism can be directly omitted from methylated promoter DNA by altering nucleosome stability or position.[2]

Regulation of DNA methylation

Regulation of DNA methylation is vast because DNMT1 is targeted by many transcription factors and can be methylated, phosphorylated and acetylated. The preservation of methyltransferase can also be altered by covalent attachment of small ubiquitin-like modifier (SUMO) proteins, a process referred to as SUMOylation. The effects of these modifications are site specific and dependent on the enzymatic players involved.[3]

X-Chromosome Inactivation

The X-Chromosome is sex chromosome in mammals. The X- Chromosome is found in males and also females. It is inherited from the individuals parents. In males you would find XY as the sex chromosomes , but in females the Y-Chromosome is replaced with an X-Chromosome meaning it would be XX as the female sex chromosomes. In females DNA methylation plays a role in the inactivation of one of the X-Chromosomes that are inherited. [4]

The first way of X-Chromosome inactivation is gamete-specific imprinting. Gamete-specific imprinting is differential modification or expression of on allele depending on whether its inheritance is via the sperm or egg, it’s the imprinting originally applied. The gamete–specific imprinting can be only found in specifically tissue, and the location of tissue is not the same in all mammals. For example in rodents, inactivation of X-Chromosome depends on gamete organ like the embryonic tissue. The embryonic tissue shows trans–genes in differences in location methylation.[5]

The second effect of DNA Methylation on X–Chromosome inactivation is by making a inactive strain, and species specific imprinting. By intermarrying different families of mammals the randomness would be close the X-chromosome . for example, when you intermarry between horse and donkey that will given a mule , the mule have mutation can't intermarry.[6]

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Third way to inactivate of X-chromosome is allele – specifically imprinting . allele mean gene come in more than one form , the different form called allele . the allele be come different because different arrangement of sequences that sometime can be mutation and effect on X- chromosome by make it inactive .that allele become inherited and go from generation to the other generation.[7]

Methylation in Cancer

An early diagnosis is important for a affective treatment for many types of cancer. The normal methods such as (cytology ,histopathology, immunohistochemistry,) are useful but molecular marker can identify the type of cancer. The methylation type can differentiate tumor types, subtypes, and might respond to chemotherapeutic agents.[8]

DNA methylation plays an important role in epigenetic, the study of heritable phenotype changes [9], modification in natural cell methylation. DNA methylation essential for gene expression and gene slicing it is also involved in histone modification, these two modification are important for genome functions by changing the chromatin structures. The enzyme that regulates the methylation modification is methyltransferases. Mutations are not the only factor of cancer, Hypermethylation can lead to cancer by inactivation of tumor suppressor genes such as p53. The Adjustment in the function of histone modification compound can disturb the levels of histones markers leading to oncogenic, gen that can cause cancer, turning to cancer cell.[10]. Hypomethylation is another type of methylation disorder that is found in many type of solid tumors such as prostate tumors and cervical cancer. A Patient with immunodeficiency are heavily hypomethylated in pericentric heterochromatin regions in chromosomes 1 and 16.[11]

DNA METHYLATION AS A detector FOR TUMOR DIAGNOSIS

The knowledge about methylation pattern in human cancer have improved in the past 4 years. The specific tumor methylation of different genes has been classified and documented. Highly advanced techniques of methylation detection include powerful tools such as sodium bisulfite conversion, cDNA microarray, restriction landmark genomic scanning, and CpG island microarrays.[12]

DNA Methylation and Aging

In recent studies, DNA methylation and aging have been heavily linked. A study coordinated by Fraga MF et al. demonstrates this exquisite link perfectly. By examining global and locus-specific variations in DNA Methylation in identical twins. The study revealed that when the identical twins where at a younger stage in life that they had identical methylomes, but more mature twins had extraordinarily diverse methylomes.[13] The condition of 27,578 CpG loci in identical twins and also in non-twins expressed that 88 sites in or close to 80 genes whose 5mC proportion had variated quite a bit with the grew older in age. The genes EDARADD, TOM1L1, and NPTX2 methylations of their CpGs are predominantly linked with age. By using two cytosines from the loci, a regression model can be used to predict with a marginal error of 5.2 years the age of the individual.[14]

The prior mentioned three genes have a distinct link with some complications related to aging. For example, EDARADD mutations maybe slow down wound healing[15], and effect the losing of teeth, hair, and sweat glands [16]. NPTX2 is overexpressed in Parkinson disease [17]. TOM1L1 is under expressed in esophageal squamous cell carcinoma(6)[18].

Conclusion

As Previously discuss, DNA Methylation plays many roles. Some of these roles are in X-Chromosomal inactivation, Cancer, and also in aging. With more understanding in how DNA Methylation executes its actions, the more we understand its links with the topics discussed above.

References

1. Fraga MF, Ballestar E, Paz MF, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005;102(30):10604–10609. doi:10.1073/pnas.0500398102 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1174919/)
2. Fraga MF, Ballestar E, Paz MF, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005;102(30):10604–10609. doi:10.1073/pnas.0500398102 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1174919/)
3. Fraga MF, Ballestar E, Paz MF, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005;102(30):10604–10609. doi:10.1073/pnas.0500398102 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1174919/)
4. Preferential X-chromosome inactivation, DNA methylation and imprinting MARILYN MONK and MARK GRANT MRC Mammalian Development Unit, Wolfson House, 4 Stephenson Way, London NW1 2HE, U (https://dev.biologists.org/content/develop/108/Supplement/55.full.pdf)
5. Preferential X-chromosome inactivation, DNA methylation and imprinting MARILYN MONK and MARK GRANT MRC Mammalian Development Unit, Wolfson House, 4 Stephenson Way, London NW1 2HE, U (https://dev.biologists.org/content/develop/108/Supplement/55.full.pdf)
6. Preferential X-chromosome inactivation, DNA methylation and imprinting MARILYN MONK and MARK GRANT MRC Mammalian Development Unit, Wolfson House, 4 Stephenson Way, London NW1 2HE, U (https://dev.biologists.org/content/develop/108/Supplement/55.full.pdf)
7. Preferential X-chromosome inactivation, DNA methylation and imprinting MARILYN MONK and MARK GRANT MRC Mammalian Development Unit, Wolfson House, 4 Stephenson Way, London NW1 2HE, U (https://dev.biologists.org/content/develop/108/Supplement/55.full.pdf)
8. DNA Methylation and Cancer, JOURNAL OF CLINICAL ONCOLOGY, VOLUME 22 NUMBER 22 NOVEMBER 15 2004, Partha M. Das and Rakesh Singal (https://pdfs.semanticscholar.org/8b39/6dee2ea72558ca395bbf942fb6736574de94.pdf)
9. Dupont C, Armant DR, Brenner CA. Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med. 2009;27(5):351–357. doi:10.1055/s-0029-1237423 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791696/)
10. Mechanisms of Ageing and Development, Volume 123, Issue 12, November 2002, Pages 1649-1654, Yasuhito Yuasa (https://www.sciencedirect.com/science/article/pii/S0047637402001008)
11. DNA Methylation and Cancer, JOURNAL OF CLINICAL ONCOLOGY, VOLUME 22 NUMBER 22 NOVEMBER 15 2004, Partha M. Das and Rakesh Singal (https://pdfs.semanticscholar.org/8b39/6dee2ea72558ca395bbf942fb6736574de94.pdf)
12. DNA Methylation and Cancer, JOURNAL OF CLINICAL ONCOLOGY, VOLUME 22 NUMBER 22 NOVEMBER 15 2004, Partha M. Das and Rakesh Singal (https://pdfs.semanticscholar.org/8b39/6dee2ea72558ca395bbf942fb6736574de94.pdf)
13. Fraga MF, Ballestar E, Paz MF, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005;102(30):10604–10609. doi:10.1073/pnas.0500398102 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1174919/)
14. Bocklandt S, Lin W, Sehl ME, et al. Epigenetic predictor of age. PLoS One. 2011;6(6):e14821. doi:10.1371/journal.pone.0014821 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120753/)
15. An Extended Epidermal Response Heals Cutaneous Wounds in the Absence of a Hair Follicle Stem Cell Contribution, Langton, Abigail K. et al. Journal of Investigative Dermatology, Volume 128, Issue 5, 1311 – 1318 (https://www.jidonline.org/article/S0022-202X(15)33839-2/fulltext)
16. Identification of a Novel Death Domain-Containing Adaptor Molecule for Ectodysplasin-A Receptor that Is Mutated in crinkled Mice, Minhong Yan, Zemin Zhang, John Ridgway Brady, Sarah Schilbach, Wayne J. Fairbrother, and Vishva M. Dixit (https://www.cell.com/current-biology/fulltext/S0960-9822(02)00687-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0960982202006875%3Fshowall%3Dtrue#secsection0015)
17. Moran LB, Hickey L, Michael GJ, et al. Neuronal pentraxin II is highly upregulated in Parkinson's disease and a novel component of Lewy bodies. Acta Neuropathol. 2008;115(4):471–478. doi:10.1007/s00401-007-0309-3 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2270353/)
18. Qi Y, Li X, Zhao L, Seykora JT. Decreased Srcasm expression in esophageal squamous cell carcinoma in a Chinese population. Anticancer Res. 2010;30(9):3535–3539. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107990/)