Female mammals have XX chromosomes and males have XY. But scientists have never understood how females decide which of their two X’s should be active in each of its cells.
A team of researchers at Massachusetts General Hospital have just solved the puzzle. Their findings were published in the journal Nature Cell Biology.
XCI stands for X Chromosome Inactivation. As female embryos develop, XCI occurs. Every gene is sorted to present itself on one of the two X chromosomes. A gene that presents on both, or on none, would result in a toxic situation for the cell. This process is vital for proper fetal development. XCI is also critical in the development of X-linked genetic diseases like Rett Syndrome.
Understanding how this process works has been a goal for the scientific community since we first understood it existed. In 2006, Jeannie Lee and her team discovered that for a moment during embryonic development, both X chromosomes pair together. Prior to this pairing, both of the chromosomes are identical. This means that they originally carry the same genes. These include Xist, a type of noncoding RNA, and Tsix, another type of RNA with blocks Xist. Tsix also prevents the XCI process.
The pairing of the chromosomes was found to be an essential step in the decision of which chromosome to make inactive. But, what lead to the ultimate decision was still a mystery.
Lee’s team continued their quest to find out the “why.” To do so, they needed to develop a more sophisticated molecular tool. This tool allowed them to investigate the individual proteins involved in the XCI process.
They uncovered the importance of an enzyme called DCP1A in the XCI process. This enzyme chooses one of the chromosomes to bind to. DCP1A only exists in very small quantities meaning it is only able to bind to one of the chromosomes. This decision is random, and makes the RNA unstable by decapping the protective cover on Tsix.
The protein called CTCF is responsible for holding the two chromosomes to each other when they are paired. After the DCP1A enzyme binds to one of the chromosomes, CTCF binds to the unstable Tsix. Once CTCF is bound to the Tsix, it forces it to permanently shut down.
Xist then completes the process of silencing that X chromosome.
What it Means
This discovery is huge because it can lead to a deeper understanding of many other molecular processes in the human body. There are many occasions when the body chooses which gene it should express, and which it should silence. A better understanding of this molecular process could lead to a greater understanding of the body as a whole, and a greater understanding of rare diseases like X-linked genetic conditions.