The silence of the X chromosomes

(Just in case, let's clarify that the "girls" X chromosomes come from both parents, that is, one of them is maternal, and the other is paternal.) However, in females, one of the X chromosomes is turned off: if they were both active, if genes from both chromosomes were working in the cells at once, then a molecular-biochemical imbalance would occur in the body. Therefore, even during intrauterine development, certain mechanisms are activated that suppress the work on one of the X chromosomes, and which one of them will turn off is determined randomly, that is, either the paternal or maternal X is turned off in different cells of the body. 

The sections of two chromosomes are colored yellow, while one of them is active,
the other is in complex with Xist-RNA (colored red) and inactive. (Photo by GENECLEANER / WIKIMEDIA.)

Although biologists have known about the inactivation of one of the female sex chromosomes for a long time, how exactly this happens has remained a mystery for a long time. Over time, it was found out that the so-called long non-coding RNAs play a leading role here. Usually, when we talk about RNA, we mean informational, or matrix, molecules that work as intermediaries between DNA and the protein-synthesizing apparatus: information about a protein molecule is copied from DNA to RNA, and already the RNA is read by ribosomes that cross-link amino acids into a polypeptide chain according to the genetic code. 

However, a huge mass of RNA does not encode any proteins, and yet the cell cannot do without them. And now we are talking about regulatory RNAs that can bind to target molecules - for example, with some sites in DNA or with proteins – and change their activity. For example, by sitting on a certain regulatory region in DNA, regulatory RNA can prohibit the synthesis of ordinary, matrix RNA on a gene controlled by this regulator – thus the gene becomes inactive. 

There are many varieties of regulatory RNAs, and one of these varieties is lnkRNA, long non–coding RNA, or long non-coding RNAs. (They were called long because they are not inferior in size to coding RNAs, including hundreds and thousands of pairs of nucleotide monomers, whereas usually regulatory RNAs do not differ in particular length and are limited at best to several dozen nucleotides.) The RNA that turns off the X chromosome is called Xist, and it refers to long non-coding. It is synthesized on one of the X chromosomes, which it turns off as it synthesizes itself. It is known that it can bind both directly to chromosomal DNA and to proteins that control the packaging and archiving of DNA. 

The chromosome in its working form is the longest and most intricate strand of DNA, which is "smeared" over a fairly large space inside the cell nucleus – its genes are free and available to proteins that synthesize RNA. To turn off either a section of the chromosome, or the whole of it, you need to literally "wind it up": tightly pack the DNA strand with the help of special proteins. 

Two years ago, researchers from the California Institute of Technology published an article describing what Xist-RNA does here: it works like a magnetic paperclip, collecting at one point different genes that need to be inactivated. When it appears, the genes cluster around it, condensing into something like a cloud. Now the proteins responsible for regulating genes do not need to look for them, it is enough to come to one specific area where all the genes that require switching off will be grouped. 

At the same time, it was possible to determine that different sections of the huge Xist-RNA are involved in the process in different ways: so, some repeating sequences turned out to be extremely important for the "silencing" of the X chromosome - if these sequences were cut out of Xist–RNA, then the chromosome worked as if nothing had happened. A new work published in Cell Reports (Monfort et al., Identification of Spen as a Crucial Factor for Xist Function through Forward Genetic Screening in Haploid Embryonic Stem Cells, in the public domain) complements the picture. Researchers from the Swiss Higher Technical School of Zurich decided to find out what the role of the X chromosome itself is in its own inactivation (Fabio Bergamin, How a female X chromosome is inactivated). In other words, they were interested in whether there are any genes in the chromosome, without which it cannot be turned off, without which Xist itself will be powerless? 

In the experiments, special stem cells of mice were used, which had only one X-chromosome and in which Xist-RNA was constantly synthesized. Such cells did not live for a long time: the accumulation of regulatory RNA completely turned off the only X-chromosome – and after all, the genes that are recorded in it are necessary for the life of the cell. However, the situation could be saved if the inactivation process was disrupted. The authors of the work alternately turned off the X-chromosomal genes: if the cells suddenly survived, it means that the chromosome was not silenced in them, that is, the disabled gene was important for the "lullification" of the X chromosomes

Several such genes were found, and Anton Wurtz and his colleagues examined the Spen gene in detail. It encodes a protein that binds to RNA, which serves as a kind of adapter between regulatory Xist and chromosomal DNA: without it, Xist-RNA does not work well. That is, such a sequence of events turns out: in order to start pulling DNA to the "packing point", regulatory RNA must arm itself with a special protein, without which its design task will be impossible. It is possible that other X-chromosome genes, necessary for inactivation of their own chromosome, function in the same way. 

Diagram from an article in Cell Reports – VM.

The system, as we can see, is very complex: not only does the X chromosome encode Xist RNA, but it also has special genes that help Xist work. Does all this matter to a person? We have both Xist and the Spen gene, so it is quite possible that the above mechanism also works in women. In general, other chromosomes can be controlled according to a similar scheme: after all, not all genes work simultaneously in a cell, some "wake up" only at certain intervals of development, and some generally "sleep" almost all their lives. Unnecessary parts of the genome can be preserved in archival form with the help of similar regulatory RNAs, and then, by studying the X chromosome, we have a chance to see how things are in other parts of the cellular genome. 

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13.08.2015