Posts Tagged ‘Methylation’

Methylation Sites on DNA

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DNA methylation is THE key driver of epigenetic regulationWhere goest CpG methylation, then followest chromatin remodellingNOT the other way around.

“The heritability of genomic methylation patterns clearly shows that once established, DNA methylation is dominant over chromatin modifications.”

Some neurodevelopmental processes (here) seem to depend on DNA methylation, but, is this the main purpose of all this methylation?


Our genome is a huge junk pile.  That’s right … we are built from a genome, of which some 40%, are old retroviruses, transposons and other broken legacies of foreign DNA that inserted themselves into the genomes of our mammalian ancestors.  These ancient viruses can be very dangerous and wreak havoc if they are allowed to be transcribed.  DNA methylation helps keep this from happening.  Its a HUGE job … some 60% of all CpG’s are methylated … likely THE main purpose of DNA methylation.

“The lack of cell-type-specific methylation at either enhancers or promoters indicates that DNA methylation is likely to have a negligible or very small role in development, and that the methylation changes seen at some low-CpG promoters are likely to be a result of transcriptional activation rather than a cause.”

“The data indicate that the bulk of the genome is methylated as the default state, and unmethylated regions are protected from a promiscuous DNA methylating system by a combination of very high CpG densities and histone modifications and variants that repel DNA methyltransferase complexes.”

So, we must keep in mind when reading the epigenetic literature (a methyl group here or there contributes to less anxiety) that there is a much more vital process happening (ie., lack of a methyl group here or there can lead to a lethal viral attack). Occasionally, in the process of keeping us alive, our physiological systems can make life difficult.  C’est la vie!

Also, it appears that methylation is like an enormous fire-hose spraying methyl groups everywhere in the genome to dampen the ground and prevent any small fires (viruses) from igniting. How much stock can you put in research findings that hinge on the appearance/disappearance of 1 or 2 errant methyl groups?

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remember a day before today
Image by DerrickT via Flickr

Most cells in your adult body are “terminally differentiated” – meaning that they have developed from stem cells into the final liver, or heart, or muscle or endothelial cell that they were meant to be.  From that point onward, cells are able to “remember” to stay in this final state – in part – via stable patterns of DNA methylation that reinforce the regulation of “the end state” of gene expression for that cell.  As evidence for this role of DNA methylation, it has been observed that levels of DNA methyl transferase (DNMT) decline when cells are fully differentiated and thus, cannot modify or disrupt their patterns of methylation.

NOT the case in the brain! Even though neurons in the adult brain are fully differentiated, levels of methyl transferases – DO NOT decline.  Why not? Afterall, we wouldn’t want our neurons to turn into liver cells, or big toe cells, would we?

One hypothesis, suggested by David Sweatt and colleagues is that neurons have more important things to “remember”.   They suggest in their fee and open research article, “Evidence That DNA (Cytosine-5) Methyltransferase Regulates Synaptic Plasticity in the Hippocampus” [doi: 10.1074/jbc.M511767200] that:

DNA methylation could have lasting effects on neuronal gene expression and overall functional state. We hypothesize that direct modification of DNA, in the form of DNA (cytosine-5) methylation, is another epigenetic mechanism for long term information storage in the nervous system.

By measuring methylated vs. unmethylated DNA in the promoter of the reelin and BDNF genes and relating this to electrophysiological measures of synaptic plasticity, the research team finds correlations between methylation status and synaptic plasticity.  More specifically, they find that zebularine (an inhibitor of DNMT) CAN block long-term potentiation (LTP), but NOT block baseline synaptic transmission nor the ability of synapses to fire in a theta-burst pattern (needed to induce LTP).

This suggests that the epigenetic machinery used for DNA methylation may have a role in the formation of cellular memory – but not in the same sense as in other cells in the body – where cells remember to remain in a terminally differentiated state.

In the brain, this epigenetic machinery may help cells remember stuff that’s more germane to brain function … you know … our memories and stuff.

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