The methylation of cytosine bases in DNA is one more mechanism of controlling how a genome (and the organism for which it codes) responds to environmental perturbation from equilibrium. Methylation has the potential to not only modify the rate of expression of various genes but also the ability to more permanently remodel the three-dimensional structure of the DNA by changing chromatin from one form to another (e.g. from euchromatin to heterochromatin).
Methylation marks that control gene expression are generally more stable than histone modification. One reason for this is that methylation is generally conserved even through mitotic cellular division with the help of maintenance methyltransferases, whereas histones are not covalent modification of the DNA and only maintain their attachment to DNA through hydrogen bonding. This weak level of bonding for some histone components allows them to shift from place to place and not stably affect gene expression. Methylation marks may actually direct the histone modification locations.
In bacteria and archaea, methylated DNA bases assist in mismatch repair systems by helping the cell determine the copy and the template strands (i.e. new and old strands, respectively).
The amplification of DNA using PCR does not preserve the methylation marks because all PCR does is make copies of templates of DNA's nucleobases. No other features (like 3-D DNA structure or non-nucleobase modifications like methylation) are preserved in the process. Although techniques have been developed to quantify and localize the sites of DNA methylation.
As Law and Jacobsen's review states, the pathways that lead to the removal of methylation are less well characterized. These pathways are essential to developmental biology.
In animals, DNA methylation is prevalent throughout the genome except in CpG islands. This review makes the claim that DNMT3A and DNMT3B establish the methylation patterns of DNA in early embryogenesis (at around the time of implantation). What is not yet been directly states is when the DNA became unmethylated. Is the DNA of gametes always unmethylated? Are germ cells that give rise to gametes unmethylated or do they become unmethylated in the course of their production? Are they completely demethylated or are only most parts of the DNA demethylated (which would lead to the possibility of imprinting)?
Wow, if I would have had the patience to read the following paragraph of the review, I would have seen the answers to some of my questions.
Following a wave of demethylation that is required to erase DNA methylation imprints established in the previous generation, DNA methylation patterns are re-established at imprinted loci and transposable elements (TE) during gametogenesis by DNMT3A and a non-catalytic paralogue, DNMT3-like.
Interactions between unmethylated H3K4 and DNMT3L have been linked to gene imprinting.
Interesting questions emerge from our growing knowledge of gene expression from DNA to post-translational modification. Are there other modifications of DNA or histone proteins that change gene expression? Fructose has been shown to be 10 times more efficacious at generating non-enzymatic glycosylation species (also called advanced glycation end products (AGEs)). Is the high level of sugars, especially fructose, that the American public is consuming leading to more AGEs and consequently a dysregulation of gene expression? In that same vein, what if high sugar levels (in the blood and in the cell) are leading to AGEs of proteins that lead to non-functional proteins, which in turn requires the up-regulation of that transcript? What are the possible consequences of abnormally high levels of transcription? One recent seminar I attended suggested that an increase in transcription of a gene (that contained a tandem repeat) could lead to slippage and a consequent 2-5 nucleotide deletion often resulting in a frame-shift mutation in the gene. What if high levels of sugar consumption were leading to these mutations?
What if sugars (especially fructose) were creating glycation products with proteins like DNMT1 and subsequently preventing hemimethylated DNA from being restored to its fully-methylated state? Then, upon cellular division, there would be a cell that was missing methylation in the correct location which could lead to the dysregulation of the expression of that gene. If that gene was necessary for tissue integrity, its disregulation could lead to cancer.
Are there intercellular communication networks with which sugar interferes through the production of AGEs? Does sugar exist in a free state in the blood and/or in the cell, or instead is the sugar bound to specific carrier molecules that transport it to where it is needed? If carrier molecules are important in glucose localization, what happens when the system is overwhelmed?
