Tsix
Tsix is a non-coding RNA gene that is antisense to the Xist RNA. Tsix binds Xist during X chromosome inactivation. Xist is expressed from one of the X chromosomes in females and serves to inactivate the other X chromosome. Tsix prevents the accumulation of Xist on one female X chromosome to maintain the active euchromatin state of the chosen chromosome. The name Tsix comes from the reverse of Xist, which stands for X-inactive specific transcript.[1]
Function in mammals
Female mammals have two X chromosomes and males have one X and one Y chromosome. The X chromosome has many active genes as opposed to the Y chromosome, which only has the SRY gene. This leads to dosage compensation problems: the two X chromosomes in the female will create twice as many gene products as the one X in the male. To mitigate this, one of the X chromosomes is inactivated in females, so that each sex only has one set of X chromosome genes. The inactive X chromosome in cells of females is visible as a Barr body under the microscope. Males do not have Barr bodies as they only have one X chromosome.
In mice and some other mammals, the maternal X chromosome is always active and the paternal X chromosome is always silenced, in a process called genomic imprinting. Xist inactivates the paternal X chromosome in female mice by condensing the chromatin, via histone methylation among other mechanisms that are currently being studied. Tsix functions here to bind complementary Xist RNA and render it non-functional. Thus, Xist does not condense chromatin on the maternal chromosome, letting it remain active. This does not occur on the paternal chromosome, and thus Xist proceeds to inactivate that chromosome.[2]
Tsix regulates X chromosome dosage compensation in female mice to prevent early embryonic mortality by a dual dose of X-linked genes.[3] Tsix allows for equal dosage of X-linked genes for both males and females by inactivating the extra X chromosome in the females.[4] The mutation of genes on maternal Tsix can cause over accumulation of Xist on both X chromosomes and cause early lethality of embryo as the two X chromosomes in females and the single X chromosome in male becomes inadvertently inactivated. However, if the paternal Tsix allele is active, it can rescue female embryos from the over-accumulation of Xist.[5]
Mutations
When one allele of Tsix in mice is null, the inactivation is skewed toward the mutant X chromosome. This is due to an accumulation of Xist that is not countered by Tsix, and causes the mutant chromosome to be inactivated. When both alleles of Tsix are null (homozygous mutant), the results are low fertility, lower proportion of female births and a reversion to random X inactivation rather than imprinting.[6]
Tsix in humans
X chromosome inactivation is random in human females, and imprinting does not occur. The deletion of a CpG island in the human Tsix gene prevents Tsix from imprinting on the X chromosomes. Instead, the human Tsix chromosome is coexpressed with the human Xist gene on the inactivated X chromosome, indicating that it does not play an important role in random X chromosome inactivation.[7] An autosome may be a more likely candidate for regulating this process in humans. The presence of Tsix in humans may be an evolutionary vestige. Alternately, it may be necessary to study cells closer to the X inactivation stage rather than older cells in order to accurately locate Tsix expression and function.[2]
Regulation in cell differentiation
In development, X chromosome inactivation is a part of cellular differentiation. This is accomplished by normal Xist function. To confer pluripotency in an embryonic stem cell, factors inhibit Xist transcription. These factors also upregulate transcription of Tsix, which serves to inhibit Xist further. This cell is then able to remain pluripotent as X inactivation is not accomplished.[8]
The marker Rex-1, as well as other members of the pluripotency network, are recruited to the Tsix promoter and transcription elongation of Tsix occurs.[8] Along with Tsix and other proteins, factor PRDM14 has been shown to also be necessary for the return to pluripotency. Assisted by Tsix, PRDM14 can associate with Xist and remove the inactivation of an X chromosome.[9]
See also
References
- ^ Lee JT, Davidow LS, Warshawsky D (1999). "Tsix, a gene antisense to Xist at the X-inactivation centre". Nat. Genet. 21 (4): 400–4. doi:10.1038/7734. PMID 10192391.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ a b Cobb K (August 17, 2002). "Not a turn-on". Science News: 100–101.
- ^ "Tsix MGI Mouse Gene Detail - MGI:1336196 - X (inactive)-specific transcript, opposite strand". Mouse Genome Informatics. The Jackson Laboratory. 20 March 2013.
- ^ Stavropoulos N, Lu N, Lee JT (2001). "A functional role for Tsix transcription in blocking Xist RNA accumulation but not in X-chromosome choice". Proc. Natl. Acad. Sci. U.S.A. 98 (18): 10232–7. doi:10.1073/pnas.171243598. PMC 56944. PMID 11481444.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Sado T, Wang Z, Sasaki H, Li E (2001). "Regulation of imprinted X-chromosome inactivation in mice by Tsix". Development. 128 (8): 1275–86. PMID 11262229.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Lee JT (2002). "Homozygous Tsix mutant mice reveal a sex-ratio distortion and revert to random X-inactivation". Nat. Genet. 32 (1): 195–200. doi:10.1038/ng939. PMID 12145659.
- ^ Migeon BR (2003). "Is Tsix repression of Xist specific to mouse?". Nat. Genet. 33 (3): 337, author reply 337–8. doi:10.1038/ng0303-337a. PMID 12610550.
- ^ Payer B, Rosenberg M, Yamaji M, Yabuta Y, Koyanagi-Aoi M, Hayashi K, Yamanaka S, Saitou M, Lee JT (2013). "Tsix RNA and the germline factor, PRDM14, link X reactivation and stem cell reprogramming". Mol. Cell. 52 (6): 805–18. doi:10.1016/j.molcel.2013.10.023. PMID 24268575.
{{cite journal}}: CS1 maint: multiple names: authors list (link)