Earlier this year, I became acquainted with Genome Alberta through their activities in social media, like those on Twitter and on their blog. Over the months that I kept up with their news and their tweets, I often read about something called “epigenetics” and new directions in that field. Epigenetics was something that I had previously heard about at a few seminars, beginning back when I was a grad student at Carleton University, and something I had also read about here and there in a few papers and reviews. In all truthfulness, though, I didn’t know much about it…

What I began to wonder, in reading all this interesting work about this fascinating field of epigenetics, was how someone with an enzymology background such as myself could gain an even greater appreciation out of it? By its very name, epigenetics sounded like something that was of interest primarily to molecular biologists and geneticists. I myself, being more of a catalytic protein man, deal with metabolic enzymes as well as signalling enzymes, like protein kinases and phosphatases. And yet, epigenetics seemed like too hot a field to ignore. The question for me was: how do enzymes figure into the regulation of our genetic code? With that, I began to develop an enzymologist’s view of epigenetics. 

Epigenetic regulation is the result of enzymes that modify chromatin

Chromatin is a complex structure of DNA and protein; proteins in this structure are mainly the histones around which DNA is wound and packed. The binding between DNA and histones is dependent upon intermolecular interactions of select chemical groups. The most easily-understood, textbook example is the interaction between histone lysines and the DNA backbone. At their termini, lysines have positively-charged amino groups that electrostatically interact with the sugar-phosphate backbone of DNA.

Being an enzyme man, I thrive on post-translational modification of proteins. Surely enough, that very concept plays a crucial role in epigenetic regulation. Post-translational modification of histone proteins, especially at lysine residues, alters DNA-histone interactions. The best-studied of these modifications is the acetylation of lysine residues; the formation of a new amide bond and the nullification of the former amine’s positive charge serves to disrupt that interaction between the histone and the DNA backbone.

Acetylation/deacetylation is certainly the most intensely-studied histone modification, but by no means is it the only one. Histones can also be phosphorylated, methylated, ubiquitinated, SUMOylated, and modified by several other biochemical ornaments. Each catalyzed by their respective protein-modifying enzymes, histones are effectively a playground for enzymologists seeking to study post-translational modifications.

Chromatin-modifying enzymes are, in turn, regulated by other enzymes

We now know about these enzymes that modify chromatin, change DNA-protein interactions and regulate gene expression. But do they constantly and randomly continue to modify chromatin with no apparent method to their madness? Clearly, this wouldn’t make physiological sense. Chromatin-modifying enzymes must be regulated in such a way that they are active only when they should be.

The answer, then, is that chromatin-modifying enzymes are themselves regulated by post-translational modification in response to cellular signalling. Just as they add chemical groups onto histone proteins, so too do they have chemical groups added onto their protein structure, altering intramolecular interactions and changing their activity. Typically, in signal transduction, protein kinases and protein phosphatases are the main players, adding and removing phosphate groups to switch enzymes on and off- though many other types of signal transduction enzymes could be involved!

Originally sceptical of how or why an enzymologist could appreciate epigenetics, I learned that there is, in fact, plenty to appreciate. When considering the enzymes that directly modify chromatin, and the various hierarchical enzymes that regulate them, it’s a wonder that I wasn’t drawn to epigenetics far earlier. And even with all I outlined, I didn’t even bother touching the most obvious enzymes of all: the DNA methyltransferases that directly modify DNA itself, and not histone proteins.

How does your field and your background allow you to perceive epigenetics?

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