.png){kind=icon}
In animals whose sex is determined by sex chromosomes, there has to be some mechanism by which the amount of X chromosome gene expression is equalized for males and females. This mechanism is known as dosage compensation. Previously we discussed mammalian X-chromosome inactivation, whereby one of the X chromosomes is inactivated so that the transcription product level is the same in both XX cells and XY cells.
In the worm Caenorhabditis elegans, dosage compensation occurs by lowering the transcription rates of both X chromosomes so that product levels are the same as those of XO individuals. This may be accomplished by causing the X chromosome of XO males to reside closer to nuclear pores than XX hermaphrodites. Here, the dosage compensation complex would impede the activation of genes (rather than repress them directly.) (Sharma and Meister 2015).
In Drosophila, the female X chromosome is not suppressed; rather, the male’s single X chromosome is hyperactivated. This “hypertranscription” is accomplished at the level of translation and is mediated by the Sxl protein. Sxl (which is made by the female cells; see earlier discussion) binds to the 5ʹ leader sequence and the 3ʹ untranslated regions of the msl2 message. The bound Sxl inhibits the attachment of msl2 mRNA to the ribosome and prevents the ribosome from getting to the mRNA coding region (Beckman et al. 2005). The result is that female cells do not produce Msl2 protein (see textbook Figure 6.12), but Msl2 is made in male cells, in which Sxl is not present. Msl2 is part of a protein-mRNA complex that targets the X chromosome and loosens its chromatin structure by acetylating histone 4 (Prayitno et al 2019). In this way, transcription factors gain access to the X chromosome at a much higher frequency in males than in females—hence, “hypertranscription.”
Interestingly, new evidence (Migeon 2021) suggests that dosage compensation in humans is influenced by the dosage of a gene on chromosome 19. This factor interacts with the X chromosome to repress XIST function on the future active X. The presence of two copies of this gene appears to be critical. the presence of three chromosome 19s is tolerated whereas duplications affecting only one chromosome 19 are not. It appears that this gene is needed to “protext” the active X from being inactivated by its own XIST long non-coding RNA.
Literature Cited
Beckman, K., M. Grskovic, F. Gebauer and M. W. Hentze. 2005. A dual inhibitory mechanism restricts Msl-2mRNA translation for dosage compensation in Drosophila. Cell 122: 529–540.
Migeon, B. R. 2021. Stochastic gene expression and chromosome interactions in protecting the human active X from silencing by XIST. Nucleus. 12(1):1-5. doi: 10.1080/19491034.2020.1850981.
Prayitno K, Schauer T, Regnard C, Becker PB. 2019. Progressive dosage compensation during Drosophila embryogenesis is reflected by gene arrangement. EMBO Rep. 20(8):e48138. doi: 10.15252/embr.201948138.
Sharma R, Meister P. Linking dosage compensation and X chromosome nuclear organization in C. elegans. Nucleus. 2015;6(4):266-72.