The Epigenome

Today, a slew of very important research papers were published in the journal Nature describing a pretty incredible feat of science - the sequencing of the epigenome (well, mostly). Most of you are probably more familiar with the sequencing of the human genome via the Human Genome Project. Led by the National Institutes of Health (NIH), this endeavor mapped all of the genes in the human body and concluded in the early 2000's. The implications of this new knowledge were pretty huge! From a better understanding of the genetic basis of cancer to more personalized drug therapies, scientists gained a very important milestone in the difficult journey of learning how our bodies work.

Today, we gained another milestone through the sequencing of the epigenome, which are the modifications on the genome that affect which genes are expressed in a given cell. Think for a moment of how diverse the cells in your body can be - some can fire electrical signals to send messages throughout the nervous system (neurons) while some are engineered to produce that insulin that controls your blood glucose (beta cells in your pancreas). The genetic material in these cells, no matter where they are, is exactly the same, give or take the occasional mutation here and there. What makes the cells different from one another are what genes are turned on and off, which is partially controlled by your epigenome.

Figure 1: The epigenome controls which genes are "unwound", revealing their information to your cells. ADAPTED FROM ILLUSTRATION BY SIGRID KNEMEYER, PREVIOUSLY ADAPTED BY LAUREN SOLOMAN

This $300 million project, again supported by the NIH, was quite challenging to say the least! With the human genome project, scientists only had to worry about one genome. The epigenome, however, differs from cell to cell, making any attempts to sequence it pretty onerous. This makes sense, as the epigenome is essential for defining an individual cell's identity! The efforts mentioned above sequenced about 111 different tissues, with more to come in the future.

So in the end, why does this matter ? Our knowledge of the epigenome will allow us to notice smaller differences between people at the molecular level, which can lead to a better understanding of what causes human disease. For example, scientists may reexamine patients with cancers caused by genetic mutations and ask themselves "what role does the epigenome play in this disease?". With insight from the now-sequenced epigenome, they may discover that certain genes are inappropriately turned "on" in cancer patients, leading to therapies that target those specific genes.

Keep an eye out for more developments in this field - they're going to be pretty monumental!

Rare Disease Spotlight - Kabuki Syndrome

If you're at all familiar with Japanese art or have been fortunate enough to visit Japan's theater scene, you're probably seen someone with Kabuki-style make up. This iconic style is characterized by dramatic, thick highlights around the eyes on top of a snow white background.

Figure 1: Some examples of Kabuki make up

In 1981, researchers from the Kanagawa Children's Medical Center in Yokohama, Japan identified a rare genetic disease that they subsequently reported on in The Journal of Pediatrics. They called the disease "Kabuki syndome", due to similarities between the appearance of the afflicted with the make up styles described above.

Figure 2: A child with Kabuki syndrome

Only 1 child in 32,000 births are diagnosed with Kabuki syndrome each year and they suffer from variety of congenital defects, ranging from hearing loss to growth deficiencies. The disease was only discovered about 30 years ago, so we lack any significant information regarding life expectancy, but there is no current indication that this disease shortens lifespan.

As with many rare disorders, the advent of robust gene sequencing techniques greatly assisted geneticists who were interested in Kabuki syndome's root biological causes. In 2010, Sarah Ng and colleagues reported that the disease was due to a mutation in a gene called MLL2. But what does this gene do? To fully explain, let's dive into a short biology lesson!

Imagine your cell. Small, healthy, and unassuming. Now, imagine a small speck in the center of that cell, about 10% of its total volume (this is normally around 6 micrometers, or six millionths of a meter). What you are now visualizing is the amount of space available for your cells to pack in all of the genetic information required to code for your entire body, which would be about two meters long if you stretched it end to end! How does your body cram all of that material into such a small space? From the perspective of the cell, it approaches this problem in the same way you would if you were packing clothes into a suitcase for a trip. The key is the way in which you pack everything!

As it turns out, DNA is wrapped very tightly around proteins called histones, which are then wound tightly around each other to form structures called chromosomes. Below is a nice illustration of how that all works:

Figure 3: Packing in the DNA!

Pretty incredible, right? As I mentioned earlier, Kabuki syndrome involves a mutation in a gene called MLL2. This gene codes for a type of enzyme called a methyltransferase, which is an enzyme that affects how tightly some of the DNA in your nucleus is wound up like in the picture above. This is important, as the DNA must be relaxed for it to be translated into proteins. When the DNA is wound up tight around histones and in chromosomes, your cells can't take a look at them because they're all covered up!

Thankfully, most of the medical issues associated with Kabuki syndrome can be helped with modern medicine. While we can't cure genetic disorders yet, science is also providing us with interesting solutions to these tough problems!