Methylation and Demethylation Mechanisms

What is Methylation

In the chemical sciences, methylation is an important process that is characterized by the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group, rather than a larger carbon chain, replacing a hydrogen atom. These terms are commonly used in chemistry, biochemistry, soil science, and the biological sciences.

In biological systems, methylation is catalyzed by enzymes, thanks to which heavy metals, gene expression, protein, and, inter alia, RNA can be porcessed. (1) More relevant for HM Institute’s work, methylation is key inthe  Health Sciences, in particular with regard to  epigenetics. (See video below)

Demethylation

The counterpart of methylation is called demethylation. While Methylation is the addition of a single carbon and three hydrogen atoms (called a methyl group) to another molecule, demethylation is the removal of a methyl group. This pathway is important for the silencing of certain genes.

Methlylation and demethlation processes is a bit like turning on and off epigenetic switches inside the body that control everything from the stress response and how the body makes energy from food, turns on brain chemistry and detoxification pathways and more.

What does Methyl groups control ?

Some of the key biological process Methyl groups govern are the following: The stress (fight-or-flight) response. The production and recycling of glutathione — the body’s master antioxidant. The detoxification of hormones, chemicals and heavy metals. The inflammation response. Genetic expression and the repair of DNA. Neurotransmitters and the balancing of brain chemistry. Energy production. The repair of cells damaged by free radicals. The immune response, controlling T-cell production, fighting infections and viruses and regulating the immune response. We can thus better understand why methylation is key insofar as optimal health and longevity are concerned.

Illustration: Detoxification of heavy metals

Biomethylation is the pathway for converting some heavy elements that can enter the food chain. For example, the biomethylation of arsenic compounds starts with the formation of methanearsonates. Thus, trivalent inorganic arsenic compounds are methylated to give methanearsonate. S-adenosylmethionine is the methyl donor. The methanearsonates are the precursors to dimethylarsonates. The reduction to methylarsonous acid followed by a second methylation follows. (1) Related pathways apply to the biosynthesis of methylmercury, that which is important to remove all of tha accumulated mercury that comes from fish, teeth, vaccines, air pollution and othe rsources.

Second Illustration: Optimizing Longevity: DNA methylation at CpG Dinucleotides

The process of aging results in a host of changes at the cellular and molecular levels, which include senescence, telomere shortening, and changes in gene expression. Epigenetic patterns also change over the lifespan, suggesting that epigenetic changes may constitute an important component of the aging process. In this perspectiv, the epigenetic mark that has been most highly studied is DNA methylation, the presence of methyl groups at CpG dinucleotides.
These dinucleotides are often located near gene promoters and associate with gene expression levels. Early studies indicated that global levels of DNA methylation increase over the first few years of life and then decrease beginning in late adulthood. Recently, with the advent of microarray and next-generation sequencing technologies, increases in variability of DNA methylation with age have been observed, and a number of site-specific patterns have been identified. It has also been shown that certain CpG sites are highly associated with age, to the extent that prediction models using a small number of these sites can accurately predict the chronological age of the donor. Together, these observations point to the existence of two phenomena that both contribute to age-related DNA methylation changes: epigenetic drift and the epigenetic clock. (2)

Discussion

Evolutionary Biology and Methylation

The evolutionary theories of mutation accumulation (MA) and disposable soma (DS) provide a possible theory for the raison d’être of human aging. To better understand the relative importance of these theories, scientists a test to identify MA and DS-consistent sites across the genome using familial DNA methylation data. Two key characteristics of DNA methylation allowed did experimentation to be attempted.  First, DNA methylation exhibits distinct and widespread changes with age, with numerous age-differentially-methylated sites observed across the genome. Second, many sites show heritable DNA methylation patterns within families, in conformity with Larmack’s non-Darwinian ideas. The scientists extended heritability predictions of MA and DS to DNA methylation, predicting that MA-consistent age-differentially-methylated sites would show increasing heritability with age, while DS-consistent sites will show the opposite. Variance components models were used to test for changing heritability of methylation with age at 48,601 age-differentially-methylated sites across the genome in 610 individuals from 176 families. The results showed that 102 sites showed significant MA-consistent increases in heritability with age, while 2,266 showed significant DS-consistent decreases in heritability. These results suggest that both MA and DS play a role in explaining aging and aging-related changes, and that while the majority of DNA methylation changes observed in aging are consistent with epigenetic drift, targeted changes exist and may mediate effects of aging-related genes. (3)

To read how to Enhance Methylation via methyl donors, click here

Reference and Precision Notes

(1). Styblo, M.; Del Razo, L. M.; Vega, L.; Germolec, D. R.; LeCluyse, E. L.; Hamilton, G. A.; Reed, W.; Wang, C.; Cullen, W. R.; Thomas, D. J. (2000). “Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells”. Archives of Toxicology74: 289–299
(2). Aging Cell. 2015 Dec;14(6):924-32. doi: 10.1111/acel.12349. Epub 2015 Apr 25.
(3). http://www.genetics.org/content/early/2017/08/30/genetics.117.300217 (Source)

 

 

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