Tsix
Tsix is an RNA gene that functions as the antisense to the Xist RNA gene during X chromosome inactivation.[1] 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 euchromatic state of the chosen chromosome. The name Tsix comes from the reverse of Xist, which stands for X-inactive specific transcript.
Function in mammals
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 imprinting. Xist inactivates the paternal X chromosome in female mice by condensing the chromatin, via 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]
Effect of Tsix mutations
When one allele of Tsix in mice is null, the inactivation is skewed toward the mutant X chromosome, since the mutant experiences accumulation of Xist that is not countered by Tsix, and thus the mutant chromosome is 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. [8]
Regulation
In development, X chromosome inactivation is a part of cellular differentiation. In an embryonic stem cell, factors conferring pluripotency inhibit Xist transcription. These facts also upregulate transcription of Tsix, which serves to inhibit Xist further. This leads to the cell remaining pluripotent as X inactivation is not accomplished. 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. [9] These are complexes present in embryonic stem cells that can reprogram X inactivation and make a cell pluripotent.
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. [10]
References
- ^ Lee, JT, LS Davidow, D. Warshawsky, and Nat Genet. "Tsix, a Gene Antisense to Xist at the X-inactivation Centre." NCBI. U.S. National Library of Medicine, 21 Apr. 1999. Web. 20 Mar. 2013. <http://www.ncbi.nlm.nih.gov/m/pubmed/10192391>.
- ^ Cobb, K. ""Not a turn-on" Science News. August 17, 2002. p100-101.
- ^ "Tsix MGI Mouse Gene Detail." Mouse Genome Informatics. The Jackson Laboratory, n.d. Web. 20 Mar. 2013. <http://www.informatics.jax.org/marker/MGI:1336196>.
- ^ Stavropoulos, Nicholas, Naifung Lu, and Jeannie T. Lee. "A Functional Role for Tsix Transcription in Blocking Xist RNA Accumulation but Not in X-chromosome Choice." A Functional Role for Tsix Transcription in Blocking Xist RNA Accumulation but Not in X-chromosome Choice. Ed. Stanley M. Gartler. Proceedings of the National Academy of Sciences of the United States of America, 8 June 2001. Web. 20 Mar. 2013. <http://www.pnas.org/content/98/18/10232.long>.
- ^ Sado, T., Z. Wang, H. Sasaki, and E. Li. "Regulation of Imprinted X-chromosome Inactivation in Mice by Tsix." NCBI. U.S. National Library of Medicine, Apr. 2001. Web. 20 Mar. 2013. <http://www.ncbi.nlm.nih.gov/m/pubmed/11262229>.
- ^ Lee, JT. "Homozygous Tsix mutant mice reveal a sex-ratio distortion and revert to random X-inactivation." Nature Genetics. Published online 29 July 2002. Nature.com.
- ^ Migeon, Barbara R. "Is Tsix Repression of Xist Specific to Mouse?" Nature.com. Nature Publishing Group, 2003. Web. 20 Mar. 2013. <http://www.nature.com/ng/journal/v33/n3/full/ng0303-337a.html>.
- ^ Cobb, K. ""Not a turn-on" Science News. August 17, 2002. p100-101.
- ^ Pablo Navarro, Andrew Oldfield, Julie Legoupi,Nicola Festuccia,Agnès Dubois,Mikael Attia,Jon Schoorlemmer,Claire Rougeulle,Ian Chambers, Philip Avner. "Molecular coupling of Tsix regulation and pluripotency." Nature.com. Nature Publishing Group, 2010. Web. 18 Mar 2014.
- ^ Payer B, Rosenberg M, Yamaji M, Yabuta Y, Koyanagi-Aoi M, Hayashi K, Yamanaka S, Saitou M, Lee JT. "Tsix RNA and the germline factor, PRDM14, link X reactivation and stem cell reprogramming." Molecular Cell, 2013 Dec 26. Web. 19 March 2014.