June 4, 2020

The Niche

Knoepfler lab stem cell blog

A layman’s guide to stem cell epigenetics: if you don’t understand epigenetics you don’t know stem cells

I know you care about stem cells and research, but do you know much about epigenetics?

You should.

If you do not understand epigenetics then you do not understand stem cells.

Don’t be put off by the complicated sounding name “epigenetics”. It’s really simple conceptually and below is your easy-to-understand guide.

Epigenetics controls nearly every aspect of the biology of every type of stem cell.

One of the areas that my lab studies is stem cell epigenetics.

While scientists may quibble about terminology, epigenetics is simply the way cells control the function of their DNA.

DNA is like a library of information stored in code. Epigenetics collectively allows (or disallows) the information in DNA to be turned into action. Cells have a Rosetta Stone-type machinery that turns the information stored in DNA into functional RNAs and proteins, but it is epigenetics that determines whether that Rosetta Stone is allowed to do its job.

DNA is a very long polymer. Think of it like a few foot long very thin piece of spaghetti.

Epigenetics has two main elements: DNA methylation and histone modifications. These elements control how the spaghetti of DNA is structured. Is it a straight line? Is it a coil with a bunch of loops? The structure of DNA determines its function.

DNA methylation is a modified form of DNA typically associated with a less active state. It makes the spaghetti strand more coiled up. So DNA methylation is a type of epigenetic function that turns the thermostat of DNA activity down.

Histone modifications come in many flavors and can either turn the DNA thermostat up or down. Histone  proteins are like the sauce and meatballs with the spaghetti. They coat it and twist it and turn it. They can straighten it. What the histones do to the DNA structure depends on how they are modified.

All of these changes directly determine how active the DNA is in specific regions (e.g. genes).

Why should you care about this in relation to stem cells?

First of all, you should know the key features of epigenetics because stem cells have unique epigenetic characteristics that make them different from other cells. If stem cells lose their own special brand of epigenetic programming they are no longer stem cells. They might become a differentiated cell or even a cancer cell. Many drugs are known to target the so-called “epigenome” (aka the global epigenetic state) of cells and there is great excitement for the use of these drugs to control cell behavior including stem cells.

Second, epigenetics is important for stem cells because of cellular reprogramming.  When scientists make iPS cells what they are really doing is reprogramming the epigenome of a non-stem cell into that of a stem cell. Remarkably, the entire cell now takes on the identity of a stem cell. What this means is that the epigenome is the master of cell behavior.

What the epigenome says (i.e. which parts of the DNA it makes active or inactive) the cell does.

Factors such as Oct4 stimulate iPS cell formation by changing the epigenetic state at specific parts of a cell’s DNA. Amazingly these changes are heritable long term even if Oct4 levels go down. In essence what Oct4 does is rewire the epigenetic state of many regions of a cell’s DNA, change the activity of those genes, and in so doing give the cell a more stem-like epigenome.

The cell in turn has no choice but to accept these changes and in turn change its behavior or die. Of course the process does not always go as one might hope and sometimes epigenetic changes are not complete so cellular reprogramming is not complete. Instead of iPS cells, you got pre-iPS cells or any of many other cell types.

So to sum up, epigenetics is nature’s way of regulating how information in DNA is translated into cell behaviors.

If you have any more questions about stem cell epigenetics, just let me know.