If you have read my previous entries on Diffused Intrinsic Pontine Gliomas (DIPG) then you know how difficult they are to treat.
200 clinical trials have been dedicated to DIPG chemotherapy drugs and none have produced survival benefits. Initially this was due to lack of tumor pathology.
Six years ago, however, Dr. Michelle Monje of Stanford and other scientists started asking DIPG families to donate tumors after patients passed. As a result, they were able to determine that 80% of DIPGs have a mutation in a protein called Histone 3. Histone 3 mutations fall under the umbrella of epigenetic changes. To understand Histone 3 and epigenetic changes, however, a slight background in DNA is needed.
DNA is often called the “blueprint of life” because it defines things like our hair and eye color. DNA itself is like a spiral staircase. The “stairs” are made up of four types of building blocks called “nucleotides.” Nucleotides have fancy names but are commonly known by their first letters: A,C,T, G. Nucleotides, like tiny magnets, attract one another and form pairs. A always attracts T whilst G always attracts C. Once connected, the pairs are held together by hydrogen bonds.
Incidentally, one strand of DNA has between 500,000-2.5 million nucleotide pairs!
The order that nucleotide pairs come in is called “sequencing.” And nucleotide pairs that function in larger groups are called “genes.” EXAMPLE: the gene for blue eyes has the sequence AAACCGGTTTAA.
One strand of DNA = 500,000-2.5 million nucleotide pairs = 20,000+ genes!
Holding the nucleotide pairs together are two opposing sugar phosphate backbones. These backbones twist, giving DNA it’s famous double helix.
Let’s now discuss how DNA is packaged to fit into a cell!
One strand of stretched out DNA is approximately 6 feet long-taller than the average American male-so how does this long strand fit into one tiny, tiny cell????????
Once 146 DNA nucleotide pairs are stacked together to make a strand of DNA, the DNA then wraps itself around proteins called histones. It’s similar to winding thread around a spool. And not only does coiling make the DNA more compact, it also tightly binds the nucleotide pairs inside.
Histones also have tails. Remember this because this will be important later on!
DNA coiled around 4 pairs of histones (H2B, H2A, H3, H4) becomes a nucleosome.
A nucleosome looks like a beaded helix when all put together.
Nucleosomes are linked together by 50 DNA nucleotide pairs. They then neatly stack up to make one long fiber “chromatin” that eventually packs into a neat, tiny chromosome.
Chromosomes further compact so they can fit inside the nucleus of a cell. A normal nucleus will have 46 chromosomes.
Before we get into epigenetics, let’s talk more about gene regulation.
Can you imagine how difficult it would be if a cell had to regulate all 20,000+ genes per DNA strand? That is too much regulation for one cell! Fortunately, histones play a major role in gene regulation. They help control what genes within our DNA gets turned on and what genes get turned off. Incidentally, scientists believe that approximately 8% of our genes are actually active!
DNA, as we learned, wraps itself around histones like a thread around a spool. How tight or how loose said strand becomes is regulated by histones. This is an extremely important role because this determines how genes are read. If DNA is loosely wrapped around histones then genes are easier to read (more expressive). If DNA is tightly wrapped then genes are harder to decode (less expressive).
Let’s quickly compare more expressive and less expressive to a chocolate chip cookie recipe.
This recipe has distinguishable words, making it easy to read and follow. Kind of like DNA that is more “expressive“!
This recipe, however, has words that are very difficult to read, making it harder to follow the directions. Kind of like DNA that is less “expressive“!
More expressive genes, however, is not always a good thing.
Enter epigenetic changes.
Changes in how genes are expressed are called epigenetic changes. When epigenetic changes occur, tiny chemicals or “tags” attach themselves directly to the DNA strand or histones. These tags can bring on modifications that either turn needed genes off or unneeded genes on. This is at the point when diseases start to occur.
There are two main types of epigenetic changes: DNA methylation and histone modification. I, however, am just going to talk about histone modifications because they apply to DIPG.
Histone modifications are when acetyl (tiny chemicals) or methyl (tiny chemicals) group attach themselves to histones’ tails. This happens when DNA is more expressed (DNA strand is loosely wound around histones), allowing histones’ tails to poke out, making it easier for tags like acetyl or methyl groups to attach themselves.
In DIPG, a mutation on histone H3 causes gene silencing. Specifically, lysine (amino acid) is replaced with methionine (another amino acid) on histones’ tails. This causes a needed gene to go silent. Ultimately normal glial cells (brain cells) begin to turn into cancer cells.
Which brings me to this loaded question: what brings on epigenetic changes?
Epigenetic changes can be caused by our environments. What we eat, where we live, the jobs we have, the amount of stress that we have-all can change how our DNA is expressed.
Let’s use identical twins Anne and Jane as examples.
When they were younger, people couldn’t tell them apart. Why? Because their DNA is exactly the same therefore they were identical in looks.
The twins’ went separate ways at age 25. Ann became a yoga instructor who ran five times a week, ate healthy foods, and enjoyed the beach. Jane stayed in Mississippi, worked a desk job for 30 years, ate Southern fried cooking, and rarely exercised.
At 70 years old, Anne is still thin, still eats healthy, but has recently been diagnosed with lupus. Jane is overweight, still eats fried food, has no symptoms of lupus but was diagnosed with cardiac disease at 60.
ANNE AND JANE HAVE ALWAYS HAD IDENTICAL DNA SO HOW DID THEY BECOME SO PHYSICALLY DIFFERENT?
Anne’s and Jane’s DNA sequences never changed through the years because DNA sequences don’t change. The same DNA that they were born with is the same DNA that they are going to die with. Their respective DNA’s, however, have been subjected to the epigenetic changes that we have been talking about.
In my next entry, I will discuss a promising new drug that addresses H3 histone mutation. In the meantime, I hope this was helpful.