Epigenetics: the foreman handling the blueprints of your DNA

Imagine we could shrink down to itsy-bitsy versions of ourselves; so small that we are smaller than a cell, so small we could be mistaken for a molecule. Stepping into the rushing superhighway of your bloodstream, we spot a monocyte floating by. Snagging an epitope, we catch a ride on the monocyte, and dive through the lipid bilayer to see what’s beneath.

Inside the cell there is an incredible bustle of activity, with proteins running up and down actin filaments, dense granules soaking up the artificial light of our imagination, and looming in the center, surrounded by it’s own lipid bilayer, lies the nucleus. This is the goal of our journey, and swinging down a microtubule, we dive through a nuclear pore into the heart of the cell.

Here we see DNA in all of its slender double-helical glory, being wrapped tightly around histones. Suddenly, you see something remarkable. A DNA methyltransferase – an enzyme which does exactly as its name suggests – carefully transfers a methyl group to a specific region of DNA.  The DNA, which had been loosely wrapped around the histones, coils tighter and becomes all but inaccessible.

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You watch with rapt fascination as a DNA Polymerase bumps uselessly against the tightly bound DNA.

This is epigentics.

If DNA is the blueprint to every cell in your body, epigenetics is the foreman on the construction site deciding exactly what blueprints are relevant to his work site.  The thing is, we have yet to come up with a way to become extremely small and peer into a cell, so unfortunately what we know about epigenetics is very limited.  If you want a great (and relatively quick) review of what epigeneticw is, one of my favorite youtube channels covered it very well in this video.

You might say, well why is epigenetics important? Well let’s say you’re you, but you’ve only been around for 1 week.  You’re developing in your mother’s womb, and your cells are multiplying and dividing, as they are wont to do.

Those cells will eventually become heart cells, skin cells, brain cells – all the various cells that make up the entity that is you.  Epigenetics is what directs those cells to differentiate into a specific cell.  It’s the foreman looking at the blueprints and yelling “alright boys! This one’s a neuron! Let’s get those dendrites sprouting!”

In a time when genetic sequencing is cheap enough for the layperson and 3D modeling of protein interactions is within our grasp, here lies an entire field of biology that has barely been scratched.  Most researchers study epigenetics through another lens: genetic, proteomic, clinical, etc.  The genetic lens is, like I said, akin to looking at blueprints and imagining how the tower can be built from them.  The proteomic lens is like looking at the tower and trying to figure out how they managed to fit it all together.  Sometimes, I think, scientists would do well to simply listen to the foreman- he knows exactly how those blueprints became that tower.

Proteins at your fingertips

e1soi
With a click and a casual flick of the wrist, a 289 kilodalton protein rotates drunkenly on its axis.  A few more clicks and the protein has transformed from a bundle of sheets and tubes to a ponderous and bulbous entity.  These are just a few of the simple and intuitive interface tools available from NCBI’s CnD3 applet.

You, yes you, can go to NCBI, download their Cn3d (“see in 3D”) application, and play with your favorite protein, all for free! I’ve spent the last two hours playing with mTOR, the bread and butter protein of my lab. You can highlight secondary structures, compare domains between proteins, and much much more. And for free! Tonight I shall be blissfully dreaming of spinning multi-colored proteins transitioning from basal to active states. What an amazing time to be alive.

Semen: The .zip file of body fluids

This morning I received an email from my boss. Subject line: “good news!” I think it takes a special kind of scientist to get very excited about the arrival of a semen sample.

You see, my lab specializes in finding mutations involved in a specific disorder: tuberous sclerosis complex (TSC). We have already found a mutation in this particular patient, and by sequencing the DNA from his semen, we can assess the frequency of that mutation in his sperm, and thus, how likely he is to pass it on.

But first, we have to get the DNA out of the sperm.

Extracting DNA from cells is a geneticists bread and butter, but this is semen we’re talking here: I wanted to be sure I didn’t have to handle it again. As it turns out, it was a good thing I did my reading, because spermatazoa are so well protected from the environment, that normal lysis protocols will not work on them. They’re basically the armored knights of cells when it comes to cracking them open.

The reason why these nuts are so tough to crack (pardon the pun) is because the DNA is linked by disulfide bonds, which my Bio 251 prof refers to as “molecular staples.” These bonds are inordinately strong, and they hold the DNA the proteins are bound on tightly together.

This special design made me curious about the manner in which DNA is packaged into sperm cells, so I investigated further. When normal cells undergo mitosis – cell division – DNA is wrapped around histones, sort of like thread around a spool. This is called chromatin, which is super compact. The aggregation of those chromatin structures forms the traditional chromosomes you might see from a karyotype.

Sperm DNA though, replaces most of the histones with different proteins (protamines), allowing the DNA to be packed even tighter. The resulting structure is so compact, it needs to be stapled together with disulfide bonds for the whole thing to be crammed into a sperm cell.

This is the molecular way of data compression. That is to say, DNA in spermatazoa are .zip files of your genome.