X inactivation and epigenetics

TITLE: X inactivation and epigenetics

TITLE: DNA review

NARRATOR: Our genetic information is encoded by the DNA double helix. When DNA is read or transcribed, one strand of the double helix serves as a template strand. The specific order of the four bases encodes genetic information, and serves as the blueprint for our genetic makeup.

Each rung of the DNA ladder is called a base pair. In total, the human genome consists of about 3 billion base pairs, and encodes about 30,000 genes.

In our cells, DNA is wrapped around proteins like thread around a spool. The structure that we see here is called a nucleosome, which consists of the DNA helix tightly coiled around histone proteins. Histones have long extensions, called histone tails, which protrude from the nucleosome core. As we will see, modifications to both the histone tails and the DNA itself are indicative of whether DNA is active or not, and this is controlled by epigenetics.

TITLE: Epigenetics and the X chromosomes

NARRATOR: Humans have 23 sets of chromosomes. The sex chromosomes, X and Y, determine the sex of an individual. Females have two X chromosomes, males have one X and one Y chromosome. Epigenetics refers to processes that instruct our cells how and when to read the DNA blueprint. As we will see, female cells use an epigenetic mechanism to inactivate or silence one of the X chromosomes in each cell to prevent abnormal development.

We are now looking at cells from a female body. A full copy of the genome is found in the nucleus of every cell. Each cell has the same 23 pairs of chromosomes. We can now see individual X chromosomes. Highlighted here are two X chromosomes from one cell. The inactive X is compact in appearance, whereas the active X occupies a much greater volume, despite the two chromosomes having the same gene content.

TITLE: X chromosomes at molecular resolution

NARRATOR: We will now take a look at each X chromosome at the molecular level, which is at approximately 1 million times magnification. 

TITLE: Active X chromosome

NARRATOR: The active chromosome has a dispersed, or open, appearance, often described as resembling beads on a string. Molecules involved in gene transcription can access open DNA. The active X chromosome has specific active histone tail modifications that tag the DNA. In the next few shots, we'll look at examples of molecules that can access the active X chromosome.

Transcription factors can bind open DNA. These proteins are important in transcription initiation. They can recruit other proteins, such as histone modifying enzymes. A new modification is added to a histone tail. Open DNA is more loosely bound to histones, which allows for nucleosome disassembly. Nucleosome remodellers can also access the active X chromosome. These proteins slide the nucleosome along DNA. Ultimately, these changes open the DNA, and allow RNA polymerase, the DNA reading enzyme, to access and transcribe DNA into messenger RNA.

TITLE: Inactive X chromosome

NARRATOR: The inactive X chromosome is more tightly bound and condensed than the active form. This means that the DNA is less accessible to molecules involved in transcription. Inactive X has modifications, including specific inactive histone tail modifications, DNA methylation, and additional structural proteins that help to zip up the DNA. Ultimately, this compact version of the chromosome is unable to be transcribed and is therefore silenced.

So let's compare the two X chromosomes directly. The active X has a dispersed or open appearance. This means the genes on this chromosome are active, or on. The inactive X has a condensed or closed appearance, meaning that the genes on this chromosome are inactive, or off. Histone tail modifications and DNA methylation are examples of epigenetic marks—modifications that distinguish between the active and inactive chromosomes.

TITLE: Epigenetic inheritance

NARRATOR: Epigenetic inheritance can be visualised by the process of X inactivation. This is a close-up of a single cell from a 100 cell embryo—an embryo which is approximately 4 days old. At this early stage of development, female embryos still have two active X chromosomes. One X chromosome is inherited from the father, the other is inherited from the mother. Around this time, the two active X chromosomes interact transiently, and one is inactivated. The other is kept active. This process is mediated by both RNAs and proteins. The inactivation of the X chromosome involves the condensing of DNA. This is marked by the change in histone tail modifications, the arrival of structural proteins which help condense the DNA, and DNA methylation.

X inactivation is complete at the end of the 100 cell stage of the embryo development. The decision of which chromosome to inactivate is surprisingly random. And individual cells can have either the maternal or paternal X chromosome remaining active. However, from this point on, each cell will remember which X chromosome it has activated, and pass this information on to its progeny as the embryo develops. This is an example of epigenetic inheritance. The same pattern is maintained into adulthood.

Let's look at the female adult. If we could visualise X inactivation on the skin, you would see a distinct pattern based on the growth and migration of the original hundred cells in the four-day-old embryo. While it is not generally visible to the naked eye in humans, you are probably familiar with this pattern as we see it regularly in calico cats. In cats, the gene that encodes coat colour is found on the X chromosome. As a result, only female cats can inherit two different coat colour genes. If this happens, she will exhibit that characteristic tortoiseshell coat because of X inactivation. 

TITLE: Why is epigenetics important?

NARRATOR: The epigenetic regulation of DNA is not peculiar to the X chromosome. In fact, it is used throughout the body to turn different genes on or off in different cell types. For example, the insulin gene is switched on in pancreatic cells where insulin is made, but is inactive elsewhere in the body. Antibody genes are active in the antibody-secreting plasma cells of the immune system, but switched off elsewhere in the body. And just as epigenetics is important for normal cell function, when things go wrong, it can lead to disease. For example, there are certain genes in our bodies that protect us from cancer, collectively called tumour suppressor genes. These genes are usually on. Some diseases can cause the aberrant inactivation of these suppressor genes, which can lead to cancer.

Scientists are trying to understand how epigenetic regulation controls normal development, and how epigenetic mistakes cause disease. By understanding the mechanisms involved in epigenetic control, they will also start to look for new treatments that will override the epigenetic marks that cause disease.