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*[[X-inactivation]]
*[[X-inactivation]]
*[[Dosage compensation]]
*[[Dosage compensation]]
*[[Tsix_(gene)]]
*[[Tsix_(gene)|Tsix]]


==References==
==References==

Revision as of 22:57, 10 May 2014

Template:PBB Xist (X-inactive specific transcript) is an RNA gene on the X chromosome of the placental mammals that acts as major effector of the X inactivation process.[1] It is a component of the Xic - X-chromosome inactivation centre[2] - along with two other RNA genes (Jpx and Ftx) and two protein genes (Tsx and Cnbp2).[3] The Xist RNA, a large (17 kb in humans)[4] transcript, is expressed on the inactive chromosome and not on the active one. It is processed in a similar way to mRNAs, through splicing and polyadenylation. However, it remains untranslated. It has been suggested that this RNA gene evolved at least partly from a protein coding gene that became a pseudogene.[5] The inactive X chromosome is coated with this transcript, which is essential for the inactivation.[6] X chromosomes lacking Xist will not be inactivated, while duplication of the Xist gene on another chromosome causes inactivation of that chromosome.[7]

Function

X inactivation is an early developmental process in mammalian females that transcriptionally silences one of the pair of X chromosomes, thus providing dosage equivalence between males and females (see dosage compensation). The process is regulated by several factors, including a region of chromosome X called the X inactivation center (XIC). The XIST gene is expressed exclusively from the XIC of the inactive X chromosome. The transcript is spliced but apparently does not encode a protein. The transcript remains in the nucleus where it coats the inactive X chromosome. Alternatively spliced transcript variants have been identified, but their full length sequences have not been determined.[1]

The functional role of the Xist transcript was first definitively demonstrated in mouse female ES cells using a novel antisense technology, called peptide nucleic acid (PNA) interference mapping. In the reported experiments, a single 19-bp antisense cell-permeating PNA targeted against a particular region of Xist RNA prevented the formation of Xi and inhibited cis-silencing of X-linked genes. The association of the Xi with macro-histone H2A is also disturbed by PNA interference mapping.[8]

X-inactivation process occurs in mice even in the absence of this gene via epigenetic regulation, but Xist is required to stabilize this silencing.[9]

Gene location

The human Xist RNA gene is located on the long (q) arm of the X chromosome. The Xist RNA gene consists of conserved repeats within its structure and is also largely localized in the nucleus.[4] The Xist RNA gene consists of an A region, which contains 8 repeats separated by U-rich spacers. The A region appears to contain two long stem-loop structures that each include four repeats.[10] An ortholog of the Xist RNA gene in humans has been identified in mice. This ortholog is a 15 kb Xist RNA gene that is also localized in the nucleus. However, the ortholog does not consist of conserved repeats.[11] The gene also consists of an Xist Inactivation Center (XIC), which plays a major role in X inactivation.[12]

Transcript organization

A region

Model of the A region of Xist showing the two stem-loop structures. The repeats are indicated by red lines and are numbered from 1 to 8. T1, T2, and V1 RNase cleavages were represented by arrows surmounted by circles, triangles, and squares, respectively. Nucleotides modified by DMS or CMCT are circled. Colours of circles and arrows indicate the yields of modifications and cleavages—red, yellow, and green for strong, medium, and low modification or cleavage, respectively. Image is taken from Maenner et al.[10]

The Xist RNA contains a region of conservation called the A region that contains up to nine repeated elements.[10] It has recently been shown that in human and mouse Xist RNAs the A region comprises two long stem-loop structures that are each composed of four repeats.[4][10] Although the exact function of the A-region is uncertain, it was shown that the entire region is needed for efficient binding to the Suz12 protein.[10]

C region

The Xist RNA directly binds to the inactive X-chromosome through a chromatin binding region of the RNA transcript. The Xist chromatin binding region was first elucidated in female mouse fibroblastic cells. The primary chromatin binding region was shown to localize to the C-repeat region. The chromatin-binding region was functionally mapped and evaluated by using an approach for studying noncoding RNA function in living cells called peptide nucleic acid (PNA) interference mapping. In the reported experiments, a single 19-bp antisense cell-permeating PNA targeted against a particular region of Xist RNA caused the disruption of the Xi. The association of the Xi with macro-histone H2A is also disturbed by PNA interference mapping.[8]

Xist Inactivation Center (XIC)

The Xist RNA gene consists of an Xist Inactivation Center (XIC), which plays a major role in Xist expression and X inactivation.[13] The XIC is located on the q arm of the X chromosome (Xq13). XIC regulates Xist in cis X inactivation, where Tsix, an antisense of Xist, downregulates the expression of Xist. The Xist promoter of XIC is the master regulator of X inactivation.[12] X inactivation plays a key role in dosage compensation.

Tsix antisense transcript

The Tsix antisense gene is a transcript of the Xist gene at the XIC center. The Tsix antisense transcript acts in cis to repress the transcription of Xist, which negatively regulates its expression. The mechanism behind how Tsix modulates Xist activity in cis is poorly understood; however, there are a few theories on its mechanism. One theory is that Tsix is involved in chromatin modification at the Xist locus and another is that transcription factors of pluripotent cells play a role in Xist repression.[14]

Regulation factors of the Xist promoter

Methylation of the Xist promotor by DNA methyl transferases

The Tsix antisense is believed to activate DNA methyl transferases that methylate the Xist promoter, in return resulting in inhibition of the Xist promoter and thus the expression of the Xist gene.[15] Methylation produces an active chromatin structure, which recruits transcriptional factors and thus allows for transcription to occur, therefore in this case the transcription of Xist.[16]

dsRNA and RNAi pathway

A dsRNA and RNAi pathway have been also proposed to play a role in regulation of the Xist Promoter. Dicer is an RNAi enzyme and it is believed to cleave the duplex of Xist and Tsix at the beginning of X inactivation, to small ~30 nucleotide RNAs, which have been termed xiRNAs, These xiRNAs are believed to be involved in repressing Xist on the probable active X chromosome based upon studies. A study was conducted where normal endogenous Dicer levels were decreased to 5%, which led to an increase in Xist expression in undifferentiated cells, thus supporting the role of xiRNAs in Xist repression.[17] The role and mechanism of xiRNAs is still under examination and debate.[citation needed]

Tsix independent mechanism

Pluripotent cells transcriptional factors

Pluripotent cells consist of transcriptional factors Nanog, Oct4 and Sox2 that seem to play a role in repressing Xist. In the absence of Tsix in pluripotent cells, Xist is repressed, where a mechanism has been proposed that these transcriptional factors cause splicing to occur at intron 1 at the binding site of these factors on the Xist gene, which inhibits Xist expression[14] A study was conducted where Nanog or Oct4 transcriptional factors were depleted in pluripotent cells, which resulted in the upregulation of Xist. From this study, it is proposed that Nanog and Oct4 are involved in the repression of Xist expression.[18]

Polycomb Repressor Complex 2 (PRC2)

PRC2 consist of a class of polycomb group proteins that are involved in catalyzing the trimethylation of histone H3 on lysine 27 (K27), which results in chromatin repression, and thus leads to transcriptional silencing. SUZ12 is component of the PRC2 and it consists of a zinc finger domain. The zinc finger domain is believed to bind to the RNA molecule.[19] The PRC2 has been observed to repress Xist expression independent of the Tsix antisense transcript, although the definite mechanism is still not known.

Dosage compensation

X inactivation plays a key role in dosage compensation mechanisms that allow for equal expression of the X and autosomal chromosomes.[20] Different species have different dosage compensation methods, with all of the methods involving the regulation of an X chromosome from one of the either sexes.[21] Some methods involved in dosage compensation to inactive one of the X chromosomes from one of the sexes are Tsix antisense gene, DNA methylation and DNA acetylation;[22] however, the definite mechanism of X inactivation is still poorly understood. If one of the X chromosomes is not inactivated or is partially expressed, it could lead to over expression of the X chromosome and it could be lethal in some cases.

Turner's Syndrome is one example of where dosage compensation does not equally express the X chromosome, and in females one of the X chromosomes is missing or has abnormalities, which leads to physical abnormalities and also gonadal dysfunction in females due to the one missing or abnormal X chromosome. Turner's syndrome is also referred to as a monosomy X condition.[23]

X inactivation cycle

Xist expression and X inactivation change throughout embryonic development. In early embryogenesis, the oocyte and sperm do not express Xist and the X chromosome remains active. After fertilization, when the cells are in the 2 to 4 cell stage, Xist transcripts are expressed randomly from one X chromosome in every cell, causing that X chromosome to become imprinted and inactivated. The cells develop into pluripotent cells (the inner cell mass) where the imprint is removed, which leads to the downregulation of Xist and thus reactivation of the inactive X chromosome. Recent data suggests that Xist activity is regulated by an anti-sense transcript.[24] The epiblast cells are then formed and they begin to differentiate, and the Xist is upregulated from either of the two X chromosomes and at random, an X is inactivated and the Xist allele is turned off in the active X chromosome. In maturing XX primordial germ cells, Xist is downregulated and X reactivation occurs once again.[25]

Disease linkage

Mutations in the XIST promoter cause familial skewed X inactivation.[1]

Interactions

XIST (gene) has been shown to interact with BRCA1.[26][27]

See also

References

  1. ^ a b c "Entrez Gene: XIST X (inactive)-specific transcript".
  2. ^ Chow JC, Yen Z, Ziesche SM, Brown CJ (2005). "Silencing of the mammalian X chromosome". Annu Rev Genomics Hum Genet. 6: 69–92. doi:10.1146/annurev.genom.6.080604.162350. PMID 16124854. Retrieved 2010-07-21.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Chureau C; Prissette M; Bourdet A; et al. (June 2002). "Comparative sequence analysis of the X-inactivation center region in mouse, human, and bovine". Genome Res. 12 (6): 894–908. doi:10.1101/gr.152902. PMC 1383731. PMID 12045143. Retrieved 2010-07-21. {{cite journal}}: Unknown parameter |author-separator= ignored (help)
  4. ^ a b c Brown CJ; Hendrich BD; Rupert JL; et al. (1992). "The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus". Cell. 71 (3): 527–42. doi:10.1016/0092-8674(92)90520-M. PMID 1423611. {{cite journal}}: Unknown parameter |author-separator= ignored (help)
  5. ^ Duret L, Chureau C, Samain S, Weissenbach J, Avner P (2006). "The Xist RNA gene evolved in eutherians by pseudogenization of a protein-coding gene". Science. 312 (5780): 1653–5. doi:10.1126/science.1126316. PMID 16778056.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Ng K, Pullirsch D, Leeb M, Wutz A (2007). "Xist and the order of silencing" (Review Article). EMBO Rep. 8 (1): 34–9. doi:10.1038/sj.embor.7400871. PMC 1796754. PMID 17203100. Figure 1 Xist RNA encompasses the X from which it is transcribed. {{cite journal}}: External link in |quote= (help)CS1 maint: multiple names: authors list (link)
  7. ^ Penny GD, Kay GF, Sheardown SA, Rastan S, Brockdorff N (1996). "Requirement for Xist in X chromosome inactivation". Nature. 379 (6561): 116–7. doi:10.1038/379131a0. PMID 8538762.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ a b Beletskii, A., Hong, Y. K., Pehrson, J., Egholm, M., & Strauss, W. M. (July 2001). "PNA interference mapping demonstrates functional domains in the noncoding RNA Xist". Proceedings of the National Academy of Sciences of the United States of America. 98 (16): 9215–9220. doi:10.1073/pnas.161173098. PMC 55400. PMID 11481485.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Kalantry S, Purushothaman S, Bowen RB, Starmer J, Magnuson T (July 2009). "Evidence of Xist RNA-independent initiation of mouse imprinted X-chromosome inactivation". Nature. 460 (7255): 647–51. doi:10.1038/nature08161. PMC 2754729. PMID 19571810.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ a b c d e Maenner S; Blaud M; Fouillen L; et al. (January 2010). Hall, Kathleen (ed.). "2-D structure of the A region of Xist RNA and its implication for PRC2 association". PLoS Biol. 8 (1): e1000276. doi:10.1371/journal.pbio.1000276. PMC 2796953. PMID 20052282. {{cite journal}}: Unknown parameter |author-separator= ignored (help)CS1 maint: unflagged free DOI (link)
  11. ^ Brockdorffa N, Ashworthb A, Graham FK, McCabea VM, Norrisa DP, Coopera PJ, Swiftb S, Rastana S (1992). "The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus=cell". Cell. 71 (3): 515–26. doi:10.1016/0092-8674(92)90519-I. PMID 1423610.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ a b Lee JT, Davidow LS, Warshawsk D (1999). "Tsix, a gene antisense to Xist at the X-inactivation centre=nature". Nature Genetics. 21 (4): 400–09. doi:10.1038/7734. PMID 10192391.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Herzing LB, Romer JT, Horn JM, Ashworth A (March 1997). "Xist has properties of the X-chromosome inactivation centre". Nature. 386 (6622): 272–5. doi:10.1038/386272a0. PMID 9069284.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ a b Senner CE, Brockdorff N (2009). "Xist gene regulation at the onset of X inactivation=genetics-development". Current opinion in genetics & development. 19 (2): 122–26. doi:10.1016/j.gde.2009.03.003. PMID 19345091.
  15. ^ Nesterova TB, Popoya BC, Norton CS, Senner CE, Tang YA, Spruce T, Rodriquez TS, Merkenschlager M, Brockdorff N (2008). "Dicer regulates Xist promoter methylation in ES cells indirectly through transcriptional control of Dnmt3=epigenetic-chromatin". 1: 2–7. PMC 257704. PMID 19014663. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  16. ^ Navarro P, Pichard S, Ciaudo C, Avner P, Rougeulle C (2005). "Tsix transcription across the Xist gene alters chromatin conformation without affecting Xist transcription: implications for x–chromsome inactivation=genes-development". Genes & Development. 19 (12): 1474–84. doi:10.1101/gad.341105. PMC 1151664. PMID 15964997.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Ogawa Yuya, Sun BK, Lee JT (2008). "Intersection of the RNA interference and X-inactivation pathways=genes-development". Science. 320 (5881): 1336–41. doi:10.1126/science.1157676. PMC 2584363. PMID 18535243.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Navarro P, Chambers I, Neisius VK, Chureau C, Morey C, Rougeulle, Avner P (2008). "Molecular Coupling of Xist Regulation and pluripotency=science". Science. 321 (5896): 1693–95. doi:10.1126/science.1160952. PMID 18802003.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Silva J, Otte AP, Wakao R, Tang YA, Endoh M, Appanah R, Nesterova TB, Napoles M, Mermoud JE, Vidal M, Koseki H, Brockdorff N (2004). "Polycomb group proteins ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation=nature-genetics". Developmental cell. 7 (5): 663–676. doi:10.1016/j.devcel.2004.10.005. PMID 15525528.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Nguyen, DK, Disteche CM (2006). "Dosage compensation of the active X chromosome in mammals=nature-genetics". Nature Genetics. 38 (1): 47–53. doi:10.1038/ng1705. PMID 16341221.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ Meyer BJ; Disteche, CM (2006). "Dosage compensation of the active X chromosome in mammals=nature-genetics". Nature Genetics. 38 (1): 47–53. doi:10.1038/ng1705. PMID 16341221.
  22. ^ Csankovszki G, Magy A, Jaenisch R (2001). "Synergism of Xist Rna, DNA Methylation, and Histone Hypoacetylation in Maintaining X chromosome Inactivation=cell-biology". The Journal of Cell Biology. 153 (4): 773–84. doi:10.1083/jcb.153.4.773. PMC 2192370. PMID 11352938.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  24. ^ Mak W, Nesterova T, Napoles M, Appanah R, Yamanaka APO, Brockdorff N (2004). "Reactivation of the paternal X chromosome in early mouse embryos=Science". Science. 303 (5658): 666–69. doi:10.1126/science.1092674. PMID 14752160.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ Nesterova TB, Mermould JE, Brockdorff N, Hilton K, McLaren A, Surani MA, Peherson J (2002). "Xist expression and macroH2A1.2 localisation in mouse primordial and pluripotent embryonic germ cells=differentiation". Differentiation; research in biological diversity. 69 (4–5): 216–25. doi:10.1046/j.1432-0436.2002.690415.x. PMID 11841480.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. ^ Ganesan S, Silver DP, Drapkin R, Greenberg R, Feunteun J, Livingston DM (January 2004). "Association of BRCA1 with the inactive X chromosome and XIST RNA". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 359 (1441): 123–8. doi:10.1098/rstb.2003.1371. PMC 1693294. PMID 15065664.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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