What the Hell? - Epigenetics

So you should all know the basics of genetics now! If you don’t read my blog post “What the Hell? - Genetics”.
 
To re-cap, your genetic code is held in a library. Each book is a gene. When the gene is “read” this creates RNA and the RNA can be translated into a protein. Genes/books can be coding genes or non-coding DNA. Your genes are made up of four letters in different sequences (A, T, G, C). You also have different sections in your library depending on the function of your cells e.g. brain, liver, skin.
 
As I’ve mentioned before, key players in your genetic code being translated into a protein are the readers or “transcription factors”. But like any library you need some way of controlling all the pesky people running around. If transcription factors could pick up any book they want as many times as they wanted you get complete chaos. This happens in cancer where transcription factors get a hold of books they shouldn’t (called oncogenes) leading to cancer cells growing uncontrollably. The “people” that control this are your librarians also known as your “epigenome”. They control what books you can access, when you can take them out and how long you can take them out for.
 
What is epigenetics?
Epigenetics by definition is any act that alters gene expression without altering the genetic code. There’s a lot more to epigenetics than just controlling gene expression but for now we’ll just discuss this area. 

I’m going to talk about two main branches or epigenetics – Histone post-translational modifications and DNA methylation.

​Your DNA is very long. In fact, if you place your entire genetic code end to end from just ONE cell it would measure a whopping 1 meter. But the nucleus, where the DNA is stored, is roughly the size of a full stop. So how is all this DNA squeezed into such a small space? Your DNA undergoes an amazing amount of packing. DNA is wrapped around structures called “histones” to form a “pearl necklace”. These individual strands are then wrapped back on each other again and again until it can fit in the nucleus as a chromosomes (see picture). You have 46 chromosomes in 23 pairs (i.e. each “X” has two sides, each side is a chromosome). 

DNA Packaging. Photo Credit: Encyclopaedia Britannica Inc. Britannica Inc, E., DNA Packaging. Available at: https://www.britannica.com/science/chromosome [Accessed February 22, 2017].

You have 22 pairs of normal chromosomes and 1 pair of sex chromosomes (XX or XY). The chromosomes are numbered by their size, where the largest pair is number 1 and the smallest pair is number 22  (see picture). 

Human Karyotype. Photo Credit: Encyclopaedia Britannica Inc. Britannica Inc, E., Karyotype; Human chromosome number. Available at: https://www.britannica.com/science/chromosome [Accessed February 22, 2017].

So we have our DNA in our nucleus as chromosomes but if all of your DNA is packaged so tight how do the readers get access? Little markers are placed on the histones, which tell the DNA to be open or closed. If the marks say “open” then the DNA unwinds from the histones allowing the readers to have access to the gene(s). ​An example of this (see picture) is called "Acetylation". An acetyl mark is added to histones. This tells the DNA to unwind, giving access to transcription factors. When the acetyl mark is removed the DNA closes up again, repressing gene expression.

Addition of acetyl group unwinds DNA, allowing gene expression. Removal of the acetyl group represses gene expression.

DNA methylation can also control gene expression. As I've told you before your genetic code is made up of four letters: A (Adenosine), T (Thymine), G (Guanine), C (Cytosine). DNA methylation happens at a C which has to be beside a G (i.e. CG). This is called a CpG site (the "p" means beside or 5' to). A methyl group is added onto the C (or cytosine). This prevents transcription factors or readers getting access to DNA, preventing gene expression (see pictures). For those that are interested a methyl group is a carbon with three hydrogens (CH3).  The methyl group is put on by a DNA methyltransferase (this is an ezyme).

For those less interested, imagine you are trying to get access to a fridge. If the door is unlocked you can get in and eat but if the door is locked you can't get in. No food for you mister! 

Gene Expression: When CpG sites are unmethylated this allows transcription factors to bind.

Gene Repression: When CpG sites are methylated this prevents transcription factors binding.

But why is this important?
Beside the fact my entire PhD is based on epigenetics......

​Back to the library. We've talked before about wanting our cells to stay the way they are. No one wants a liver cell in their eye. Epiegenetics controls this. The librarians tell the readers what books they can access. They create the sections of books for different cell types and the barriers to prevent skin cells from acting like stomach cells (you'd excrete a lot of acid and mucus from your arms...gross). They also control how many times you can access the book - if you want a book to only be read once or all the time (house keeping genes) and how many copies of the book you take out. This is important for many diseases especially for cancer. In each cell you have two copies of a gene. Usually you only need one copy to be functional to live. But if your cells decide to express both copies this could lead to massive changes in the growth of the cell. For example, there is a gene called IGF2 which is important in growth and development. But we only want ONE copy of this gene. Two copies would be like super sizing all your meals. You are going to get very fat very quickly. IGF2 is one of these "oncogenes" I mentioned earlier. Loss of epigenetic marks around the second copy of this gene can lead to massive increases in tumour cell growth. 

Cancer is a very clever reader and can trick librarians. It can cause librarians to be distracted, allowing the cancer cell access to genes it shouldn't be allowed near (this can be loss of DNA methylation or hypomethylation) OR it can make the librarians super strict and shut down access to genes a normal cell would have access to (this can be gain of methylation or hypermethylation). Hypomethylation tends to happen to genes that will help cancer cells while hypermethylation tends to happen to genes that will hinder cancer cells.

There are other areas of epigenetics I haven't covered, like microRNAs and also the other roles of epigenetic modifications besides gene expression control. For now this is just a brief introduction to get you familiar with the basic ideas of epigenetics.  If you have any questions or want more detail please don't hesitate to contact me!!