Tsix
Tsix is a gene that functions as the antisense to the Xist gene during X chromosome inactivation.[1] Tsix controls X chromosome inactivation by preventing the accumulation of Xist on one female X chromosome to maintain the active euchromatic state of the chosen chromosome.
Function in mice
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. 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]
Regulation
In an embryonic stem cell, factors conferring pluripotency inhibit Xist transcription, as well as upregulate transcription of Tsix, which is an inhibitor of Xist. 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. These are complexes present in embryonic stem cells that can reprogram X inactivation and make a cell pluripotent. [6]
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. [7]
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. [8]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. [9]
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>.
- ^ 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.
- ^ 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.