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Geneticists have revealed the mechanism of suppression of the second X chromosome in women
Sergey Vasiliev, Naked Science
In humans, as in other mammals, males and females differ in a set of chromosomes. The appearance of males is determined by the presence of a small sex chromosome Y, females do not have it, and they carry two copies of the sex chromosome X. The parallel operation of two X chromosomes leads to the fact that the proteins encoded by them are produced in double quantities, disrupting the balance necessary for the normal functioning of the body. Therefore, one of them (the paternal one) is inactivated even at the first stages of embryonic development.
The key role in this process is played by the Xist gene, which is launched on the inactive X chromosome. It encodes not protein molecules, but RNA. Attracting a number of additional proteins, Xist-RNAs cling to the chromosome, connecting to it at many sites, and block gene transcription. However, many details of X-chromosome inactivation remain a mystery, and even SPEN partner proteins were identified only a few years ago.
Among them was the protein SPEN, involved in the regulation of the genome. It was studied by scientists from the head office of the European Laboratory of Molecular Biology (EMBL) in Heidelberg. Article Edith Heard and her team published in the journal Nature (Dossin et al., SPEN integrates transcriptional and epigenetic control of X-inactivation), briefly about this work is described in the press release of EMBL.
Protein SPEN (green) in living cells.
The authors conducted experiments with embryonic stem cells in which SPEN activity was suppressed. The work demonstrated that inactivation of the X chromosome does not occur. Then, and in experiments on live models, it was shown that SPEN suppressor proteins are critically needed to suppress the activity of many genes. Scientists followed their work with the help of fluorescent tags.
The mechanism of operation of SPEN. The protein recognizes promoters ("starters") and enhancers ("enhancers") of active genes, as well as related proteins (RNA polymerase Pol II). The Xist/SPEN complex binds and attracts proteins to work for the final "shutdown" of the gene, after which it is disconnected.
As soon as Xist is launched, SPEN forms a complex with its RNA. This complex recognizes the active genes of the X chromosome and binds to them. He recognizes such sites, among other things, by characteristic protein complexes that provide transcription of active genes, such as RNA polymerase II. An extremely ancient site of the SPEN protein, the SPOC domain, plays a crucial role in this interaction.
By "sitting" on DNA, Xist/SPEN stimulates the binding of proteins of the next stage of inactivation, such as the NuRD complex. These proteins produce chromatin remodeling, changing the "packaging" of DNA and – as a result – its activity. Histone acetylase HDAC3 can also come into play, which removes acetyl groups that serve as markers of active genes. Finally, the regulatory molecules detach, and the corresponding genes on the X chromosome remain "off" for the rest of their lives.
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