XIST (gene)

From Wikipedia, the free encyclopedia
  (Redirected from Xist)
Jump to: navigation, search
X inactive specific transcript (non-protein coding)
Symbols XIST ; DXS1089; DXS399E; LINC00001; NCRNA00001; SXI1; swd66
External IDs OMIM314670 MGI98974 GeneCards: XIST Gene
Species Human Mouse
Entrez 7503 213742
Ensembl ENSG00000229807 ENSMUSG00000086503
UniProt n/a n/a
RefSeq (mRNA) n/a n/a
RefSeq (protein) n/a n/a
Location (UCSC) Chr X:
73.82 – 73.85 Mb
Chr X:
100.66 – 100.68 Mb
PubMed search [1] [2]

Xist (X-inactive specific transcript) is an RNA gene on the X chromosome of the placental mammals that acts as a 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]


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[edit]

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[edit]

A region[edit]

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.[10][4] 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[edit]

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)[edit]

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[edit]

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 of the Xist promoter[edit]


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[edit]

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 mechanisms[edit]

Pluripotent cell transcriptional factors[edit]

Pluripotent stem 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[edit]

Polycomb repressor complex 2 (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[edit]

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 inactivate 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[edit]

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[edit]

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


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

See also[edit]


  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". Annual Review of Genomics and Human Genetics 6: 69–92. doi:10.1146/annurev.genom.6.080604.162350. PMID 16124854. 
  3. ^ Chureau C, Prissette M, Bourdet A, Barbe V, Cattolico L, Jones L, Eggen A, Avner P, Duret L (Jun 2002). "Comparative sequence analysis of the X-inactivation center region in mouse, human, and bovine". Genome Research 12 (6): 894–908. doi:10.1101/gr.152902. PMC 1383731. PMID 12045143. 
  4. ^ a b c Brown CJ, Hendrich BD, Rupert JL, Lafrenière RG, Xing Y, Lawrence J, Willard HF (Oct 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. 
  5. ^ Duret L, Chureau C, Samain S, Weissenbach J, Avner P (Jun 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. 
  6. ^ Ng K, Pullirsch D, Leeb M, Wutz A (Jan 2007). "Xist and the order of silencing" (Review Article). EMBO Reports 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. 
  7. ^ Penny GD, Kay GF, Sheardown SA, Rastan S, Brockdorff N (Jan 1996). "Requirement for Xist in X chromosome inactivation". Nature 379 (6561): 131–7. doi:10.1038/379131a0. PMID 8538762. 
  8. ^ a b Beletskii A, Hong YK, Pehrson J, Egholm M, Strauss WM (Jul 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): 9215–20. doi:10.1073/pnas.161173098. PMC 55400. PMID 11481485. 
  9. ^ Kalantry S, Purushothaman S, Bowen RB, Starmer J, Magnuson T (Jul 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. 
  10. ^ a b c d e Maenner S, Blaud M, Fouillen L, Savoye A, Marchand V, Dubois A, Sanglier-Cianférani S, Van Dorsselaer A, Clerc P, Avner P, Visvikis A, Branlant C (Jan 2010). Hall K, ed. "2-D structure of the A region of Xist RNA and its implication for PRC2 association". PLoS Biology 8 (1): e1000276. doi:10.1371/journal.pbio.1000276. PMC 2796953. PMID 20052282. 
  11. ^ Brockdorff N, Ashworth A, Kay GF, McCabe VM, Norris DP, Cooper PJ, Swift S, Rastan S (Oct 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 71 (3): 515–26. doi:10.1016/0092-8674(92)90519-I. PMID 1423610. 
  12. ^ a b Lee JT, Davidow LS, Warshawsky D (Apr 1999). "Tsix, a gene antisense to Xist at the X-inactivation centre". Nature Genetics 21 (4): 400–4. doi:10.1038/7734. PMID 10192391. 
  13. ^ Herzing LB, Romer JT, Horn JM, Ashworth A (Mar 1997). "Xist has properties of the X-chromosome inactivation centre". Nature 386 (6622): 272–5. doi:10.1038/386272a0. PMID 9069284. 
  14. ^ a b Senner CE, Brockdorff N (Apr 2009). "Xist gene regulation at the onset of X inactivation". Current Opinion in Genetics & Development 19 (2): 122–6. doi:10.1016/j.gde.2009.03.003. PMID 19345091. 
  15. ^ Nesterova TB, Popova BC, Cobb BS, Norton S, Senner CE, Tang YA, Spruce T, Rodriguez TA, Sado T, Merkenschlager M, Brockdorff N (2008). "Dicer regulates Xist promoter methylation in ES cells indirectly through transcriptional control of Dnmt3a". Epigenetics & Chromatin 1 (1): 2. doi:10.1186/1756-8935-1-2. PMC 257704. PMID 19014663. 
  16. ^ Navarro P, Pichard S, Ciaudo C, Avner P, Rougeulle C (Jun 2005). "Tsix transcription across the Xist gene alters chromatin conformation without affecting Xist transcription: implications for X-chromosome inactivation". Genes & Development 19 (12): 1474–84. doi:10.1101/gad.341105. PMC 1151664. PMID 15964997. 
  17. ^ Ogawa Y, Sun BK, Lee JT (Jun 2008). "Intersection of the RNA interference and X-inactivation pathways". Science 320 (5881): 1336–41. doi:10.1126/science.1157676. PMC 2584363. PMID 18535243. 
  18. ^ Navarro P, Chambers I, Karwacki-Neisius V, Chureau C, Morey C, Rougeulle C, Avner P (Sep 2008). "Molecular coupling of Xist regulation and pluripotency". Science 321 (5896): 1693–5. doi:10.1126/science.1160952. PMID 18802003. 
  19. ^ de Napoles M, Mermoud JE, Wakao R, Tang YA, Endoh M, Appanah R, Nesterova TB, Silva J, Otte AP, Vidal M, Koseki H, Brockdorff N (Nov 2004). "Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation". Developmental Cell 7 (5): 663–76. doi:10.1016/j.devcel.2004.10.005. PMID 15525528. 
  20. ^ Nguyen DK, Disteche CM (Jan 2006). "Dosage compensation of the active X chromosome in mammals". Nature Genetics 38 (1): 47–53. doi:10.1038/ng1705. PMID 16341221. 
  21. ^ Nguyen DK, Disteche CM (Jan 2006). "Dosage compensation of the active X chromosome in mammals". Nature Genetics 38 (1): 47–53. doi:10.1038/ng1705. PMID 16341221. 
  22. ^ Csankovszki G, Nagy A, Jaenisch R (May 2001). "Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation". The Journal of Cell Biology 153 (4): 773–84. doi:10.1083/jcb.153.4.773. PMC 2192370. PMID 11352938. 
  23. ^ Chenga MK, Nguyena KD, Disteche CM (2006). "Dosage compensation of the X chromosome and Turner syndrome=International-Congress-series" 1298. pp. 3–8. 
  24. ^ Mak W, Nesterova TB, de Napoles M, Appanah R, Yamanaka S, Otte AP, Brockdorff N (Jan 2004). "Reactivation of the paternal X chromosome in early mouse embryos". Science 303 (5658): 666–9. doi:10.1126/science.1092674. PMID 14752160. 
  25. ^ Nesterova TB, Mermoud JE, Hilton K, Pehrson J, Surani MA, McLaren A, Brockdorff N (Jan 2002). "Xist expression and macroH2A1.2 localisation in mouse primordial and pluripotent embryonic germ cells". Differentiation; Research in Biological Diversity 69 (4-5): 216–25. doi:10.1046/j.1432-0436.2002.690415.x. PMID 11841480. 
  26. ^ Ganesan S, Silver DP, Drapkin R, Greenberg R, Feunteun J, Livingston DM (Jan 2004). "Association of BRCA1 with the inactive X chromosome and XIST RNA". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 359 (1441): 123–8. doi:10.1098/rstb.2003.1371. PMC 1693294. PMID 15065664. 
  27. ^ Ganesan S, Silver DP, Greenberg RA, Avni D, Drapkin R, Miron A, Mok SC, Randrianarison V, Brodie S, Salstrom J, Rasmussen TP, Klimke A, Marrese C, Marahrens Y, Deng CX, Feunteun J, Livingston DM (Nov 2002). "BRCA1 supports XIST RNA concentration on the inactive X chromosome". Cell 111 (3): 393–405. doi:10.1016/S0092-8674(02)01052-8. PMID 12419249. 

Further reading[edit]

External links[edit]