XIST
XIST | ||||||
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RefSeq (mRNA) |
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RefSeq (protein) |
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Location (UCSC) | Chr X: 73.82 – 73.85 Mb | Chr X: 102.5 – 102.53 Mb | ||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Xist (X-inactive specific transcript) is a non-coding RNA transcribed from the X chromosome of the placental mammals that acts as a major effector of the X-inactivation process.[5] It is a component of the Xic – X-chromosome inactivation centre[6] – along with two other RNA genes (Jpx and Ftx) and two protein genes (Tsx and Cnbp2).[7]
The Xist RNA, a large (17 kb in humans)
The human Xist gene was discovered by Andrea Ballabio through a cDNA library screening and then characterized in collaboration with Carolyn J. Brown and Hunt Willard.[12][13]
Function
The functional role of the Xist transcript was 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.[14] The X-inactivation process occurs in mice even in the absence of this gene via epigenetic regulation, but Xist is required to stabilize this silencing.[15]
In addition to being expressed in nearly all females, XIST is expressed in narrow developmental contexts in males including human preimplantation embryos, primordial germ cells, testicular germ cell tumors, and a subset of male cancers of diverse lineages.[16] It may be involved in the dosage compensation of supernumerary X chromosomes in the latter two cases.
Gene location
The human Xist RNA gene is located on the long (q) arm of the X chromosome. The Xist RNA gene contains conserved repeats within its structure. Its gene product is largely localized in the nucleus.[8] The Xist RNA gene features a conserved A region, which contains 8 repeats separated by U-rich spacers. The A region appears to encode two long stem-loop RNA structures that each include four repeats.[17] An ortholog of the Xist RNA gene in humans has been identified in mice.[18][19] This ortholog encodes a 15 kb Xist transcript that is also localized in the nucleus. However, the ortholog does not feature conserved repeats.[20] The Xist RNA gene is located within the Xist Inactivation Center (XIC), which plays a major role in X-inactivation.[21]
Transcript organization
A region
The Xist RNA contains a region of conservation called the repeat A (repA) region that contains up to nine repeated elements.[17] It was initially suggested that repA repeats could fold back on themselves to form local intra-repeat stem-loop structures. Later work using in vitro biochemical structure probing proposed several inter-repeat stem-loop structures.[8][17] A recent study using in vivo biochemical probing and comparative sequence analysis proposed a revision of the repA structure model that includes both intra-repeat and inter-repeat folding found in previous models as well as novel features (see Figure). In addition to its agreement with the in vivo data, this revised model is highly conserved in rodents and mammals (including humans) suggesting functional importance for repA structure. Although the exact function of the repA region is uncertain, it was shown that the entire region is needed for efficient binding to the Suz12 protein.[17]
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.[14]
X-inactivation centre (XIC)
The Xist RNA gene lies within the X-inactivation centre (XIC), which plays a major role in Xist expression and X-inactivation.[22] 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.[21] 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.[23] 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.[24]
Regulation of the Xist promoter
Methylation
The Tsix antisense is believed to activate DNA
dsRNA and RNAi
A
Tsix independent mechanisms
Pluripotent cell transcriptional factors
Polycomb repressive complex
Polycomb repressive 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. Xist RNA recruits polycomb complexes to the inactive X chromosome at the onset of XCI.[29] SUZ12 is a component of the PRC2 and contains a zinc finger domain. The zinc finger domain is believed to bind to the RNA molecule.[30] 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
X-inactivation cycle
Xist expression and X-inactivation change throughout embryonic development. In early embryogenesis, the
Disease linkage
Mutations in the XIST promoter cause familial skewed X-inactivation.[5]
Interactions
XIST has been shown to
See also
- X-inactivation
- Dosage compensation
- Tsix
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000229807 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000086503 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c "Entrez Gene: XIST X (inactive)-specific transcript".
- PMID 16124854.
- PMID 12045143.
- ^ S2CID 13141516.
- S2CID 28145201.
- PMID 17203100.
Figure 1 Xist RNA encompasses the X from which it is transcribed.
- S2CID 4329368.
- S2CID 4332325.
- S2CID 21881827.
- ^ PMID 11481485.
- PMID 19571810.
- PMID 36356577.
- ^ PMID 20052282.
- S2CID 4239301.
- S2CID 4342551.
- S2CID 19889657.
- ^ S2CID 30636065.
- S2CID 4371247.
- S2CID 30636065.
- ^ PMID 19345091.
- PMID 19014663.
- PMID 15964997.
- PMID 18535243.
- S2CID 42703823.
- PMID 18974356.
- PMID 15525528.
- ^ S2CID 2898893.
- PMID 11352938.
- .
- S2CID 37749083.
- S2CID 32840485.
- PMID 15065664.
- S2CID 372211.
Further reading
- Brown CJ, Ballabio A, Rupert JL, Lafreniere RG, Grompe M, Tonlorenzi R, Willard HF (January 1991). "A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome". Nature. 349 (6304): 38–44. S2CID 4332325.
- Brown CJ, Lafreniere RG, Powers VE, Sebastio G, Ballabio A, Pettigrew AL, Ledbetter DH, Levy E, Craig IW, Willard HF (January 1991). "Localization of the X inactivation centre on the human X chromosome in Xq13". Nature. 349 (6304): 82–4. S2CID 4360783.
- Clemson CM, McNeil JA, Willard HF, Lawrence JB (February 1996). "XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure". The Journal of Cell Biology. 132 (3): 259–75. PMID 8636206.
- Hendrich BD, Plenge RM, Willard HF (July 1997). "Identification and characterization of the human XIST gene promoter: implications for models of X chromosome inactivation". Nucleic Acids Research. 25 (13): 2661–71. PMID 9185579.
- Plenge RM, Hendrich BD, Schwartz C, Arena JF, Naumova A, Sapienza C, Winter RM, Willard HF (November 1997). "A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation". Nature Genetics. 17 (3): 353–6. S2CID 23338176.
- Hong YK, Ontiveros SD, Strauss WM (March 2000). "A revision of the human XIST gene organization and structural comparison with mouse Xist". Mammalian Genome. 11 (3): 220–4. S2CID 21921352.
- Hall LL, Byron M, Sakai K, Carrel L, Willard HF, Lawrence JB (June 2002). "An ectopic human XIST gene can induce chromosome inactivation in postdifferentiation human HT-1080 cells". Proceedings of the National Academy of Sciences of the United States of America. 99 (13): 8677–82. PMID 12072569.
- 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 (November 2002). "BRCA1 supports XIST RNA concentration on the inactive X chromosome". Cell. 111 (3): 393–405. S2CID 372211.
- Kawakami T, Okamoto K, Sugihara H, Hattori T, Reeve AE, Ogawa O, Okada Y (April 2003). "The roles of supernumerical X chromosomes and XIST expression in testicular germ cell tumors". The Journal of Urology. 169 (4): 1546–52. PMID 12629412.
- Pugacheva EM, Tiwari VK, Abdullaev Z, Vostrov AA, Flanagan PT, Quitschke WW, Loukinov DI, Ohlsson R, Lobanenkov VV (April 2005). "Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation". Human Molecular Genetics. 14 (7): 953–65. PMID 15731119.
- Vasques LR, Stabellini R, Xue F, Tian XC, Soukoyan M, Pereira LV (2007). "XIST repression in the absence of DNMT1 and DNMT3B". DNA Research. 12 (5): 373–8. PMID 16769694.
- Cohen HR, Panning B (August 2007). "XIST RNA exhibits nuclear retention and exhibits reduced association with the export factor TAP/NXF1". Chromosoma. 116 (4): 373–83. S2CID 7947134.
- Chow JC, Hall LL, Baldry SE, Thorogood NP, Lawrence JB, Brown CJ (June 2007). "Inducible XIST-dependent X-chromosome inactivation in human somatic cells is reversible". Proceedings of the National Academy of Sciences of the United States of America. 104 (24): 10104–9. PMID 17537922.
- Vincent-Salomon A, Ganem-Elbaz C, Manié E, Raynal V, Sastre-Garau X, Stoppa-Lyonnet D, Stern MH, Heard E (June 2007). "X inactive-specific transcript RNA coating and genetic instability of the X chromosome in BRCA1 breast tumors". Cancer Research. 67 (11): 5134–40. PMID 17545591.
- Plath K, Mlynarczyk-Evans S, Nusinow DA, Panning B (2002). "Xist RNA and the mechanism of X chromosome inactivation". Annual Review of Genetics. 36: 233–78. PMID 12429693.
- Brockdorff N (July 2002). "X-chromosome inactivation: closing in on proteins that bind Xist RNA". Trends in Genetics. 18 (7): 352–8. PMID 12127775.
- Panning B, Dausman J, Jaenisch R (September 1997). "X chromosome inactivation is mediated by Xist RNA stabilization". Cell. 90 (5): 907–16. S2CID 17987743.
- Chaumeil J, Le Baccon P, Wutz A, Heard E (August 2006). "A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced". Genes & Development. 20 (16): 2223–37. PMID 16912274.
- Brockdorff N, Ashworth A, Kay GF, Cooper P, Smith S, McCabe VM, Norris DP, Penny GD, Patel D, Rastan S (May 1991). "Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome". Nature. 351 (6324): 329–31. S2CID 4342551.
- Sado T, Brockdorff N (January 2013). "Advances in understanding chromosome silencing by the long non-coding RNA Xist". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 368 (1609): 20110325. PMID 23166390.
- PMID 23704542.
External links
- NCBI Xist entry
- lncRNAdb Xist entry Archived 2015-12-22 at the Wayback Machine