Entry - *314670 - X INACTIVATION-SPECIFIC TRANSCRIPT; XIST

Mammalian XX females equalize gene dosage relative to XY males by inactivation of 1 of their X chromosomes in each cell. Inactivation begins at the X chromosome inactivation center (XIC), which contains several genetic elements essential for inactivation, including the XIST gene. Initiation of X chromosome inactivation requires cis accumulation of the large nontranslated XIST RNA, which coats the X chromosome, followed by epigenetic changes on the future inactive X chromosome. In somatic cells, the inactivated X chromosome is visible as the Barr body (van den Berg et al., 2009).

▼ Cloning and Expression

Brown et al. (1991) isolated a XIST cDNA from a female placenta cDNA library. XIST cDNA probes showed hybridization to RNA prepared from female samples or from somatic cell hybrids containing an inactive human X chromosome, but not to RNA from males or from hybrids containing only an active human X chromosome. Northern blot analysis showed multiple XIST transcripts, most of which were over 10 kb. RT-PCR detected multiple XIST transcripts in all female tissues tested, including heart, muscle, brain, kidney, liver, fibroblasts, and lymphoblasts. Brown et al. (1991) considered that the XIST gene is either involved in or uniquely influenced by the process of X inactivation.

Brown et al. (1992) isolated more than 70 human XIST cDNAs that yielded a 17-kb consensus cDNA. Examination of XIST cDNA clones and RT-PCR analysis revealed extensive alternative splicing. XIST lacks any significant conserved ORFs and does not appear to encode a protein. The XIST sequence includes several tandem repeats, the most 5-prime of which are evolutionarily conserved. RT-PCR and FISH experiments confirmed that XIST was expressed only from the inactive X chromosome. FISH experiments localized XIST RNA within the nucleus in a position indistinguishable from the X inactivation-associated Barr body.

By EST database analysis, followed by PCR amplification of female-specific cDNA libraries, Hong et al. (2000) extended the human XIST sequence in the 3-prime direction and found that the full-length RNA is about 19.3 kb long. The additional 3-prime sequence contains an adenosine-rich stretch and shares a high degree of conservation with the 3-prime end of mouse Xist. Hong et al. (2000) also found evidence that the 3-prime region is subject to alternative splicing. PCR analysis detected expression of the XIST 3-prime sequence in female cells only, and RNA-FISH confirmed its localization on Xi in human female fibroblasts.

Borsani et al. (1991) isolated and characterized murine Xist. Using an interspecific Mus spretus/Mus musculus domesticus F-1 hybrid mouse carrying an X;16 translocation, Brockdorff et al. (1991) showed that mouse Xist is exclusively expressed from the inactive X chromosome. They suggested that XIST and its mouse homolog are involved in X chromosome inactivation.

Brockdorff et al. (1992) analyzed mouse Xist. The mature inactive X-specific transcript is 15 kb long and contains no conserved ORFs. A number of regions of the Xist sequence comprise tandem repeats. Comparison with human XIST showed significant conservation of sequence and structure. Brockdorff et al. (1992) found that the Xist RNA in the mouse was not associated with the translational machinery of the cell and was located almost exclusively in the nucleus.

▼ Gene Structure

Brown et al. (1992) determined that the XIST gene contains at least 8 exons.

Lafreniere et al. (1993) demonstrated that the transcriptional orientation of XIST is cen--3-prime--XIST--5-prime--qter.

Hong et al. (2000) extended the XIST sequence and discovered an additional 3-prime exon and 7 polyadenylation signal sequences in the 3-prime end. The 3-prime end of human XIST shares a high degree of conservation with the 3-prime end of mouse Xist, which apparently lacks the intron Hong et al. (2000) identified in human.

Nora et al. (2012) used chromosome conformation capture carbon copy (5C) and super-resolution microscopy to analyze the spatial organization of a 4.5-Mb region including XIST. They discovered a series of discrete 200-kb to 1-Mb topologically associating domains (TADs), present both before and after cell differentiation and on the active and inactive X. TADs align with, but do not rely on, several domainwide features of the epigenome, such as H3K27me3 (trimethylation at lys27 of histone 3) or H3K9me2 blocks and lamina-associated domains. TADs also align with coordinately regulated gene clusters. Disruption of a TAD boundary causes ectopic chromosomal contacts and long-range transcriptional misregulation. The Xist/Tsix sense/antisense unit illustrates how TADs enable the spatial segregation of oppositely regulated chromosomal neighborhoods, with the respective promoters of Xist and Tsix lying in adjacent TADs, each containing their known positive regulators. Nora et al. (2012) identified a novel distal regulatory region of Tsix within its TAD, which produces a long intervening RNA, Linx. Nora et al. (2012) concluded that, in addition to uncovering a new principle of cis-regulatory architecture of mammalian chromosomes, their study sets the stage for the full genetic dissection of the X-inactivation center.

▼ Mapping

XIST Gene

By in situ hybridization, Brown et al. (1991) mapped the XIST gene to chromosome Xq13, at the interface of bands Xq13 and q21.1. The order of loci around XIST appeared to be cen--AR (313700)--CCG1 (TAF1; 313650)--PHKA (311870)--XIST--PGK1 (311800)--tel.

Borsani et al. (1991) found that mouse Xist is located in the mouse X inactivation center region. Brockdorff et al. (1991) likewise found that mouse Xist maps to the XIC region.

X Inactivation Center

Therman et al. (1974) suggested that condensation of the inactive X chromosome occurs around a center (locus) on the long arm of the X chromosome near the centromere. They based this on the observations that (1) the abnormal X chromosomes with the assumed center in duplicate form have bipartite Barr bodies, and (2) no X short arm isochromosomes (Xpi) had been confidently identified. They suggested that Xpi is lethal because the cell has no method of dosage compensation. The existence of such a locus in man was rendered plausible by the demonstration in the mouse of a locus called Xce (300074).

From studies of 5 cases of structural anomalies involving the X chromosomes, Mattei et al. (1981) concluded that the X chromosome possesses only 1 inactivation center, which is probably situated between Xq11.2 and Xq21.1.

Flejter et al. (1984) found that the most frequent site of a bend in mitotic metaphase chromosomes is Xq13.3-q21.1. It was observed in 1 member of the X chromosome pair in 63% of 46,XX cells, and in only 2% of 46,XY cells. RBG-staining showed that this specific bend is confined to the lyonized X chromosome. The observations on cells from normal persons were confirmed by studies of cells from 9 subjects with different X-chromosome abnormalities. Noting that the 'center for Barr body condensation' has been localized to the segment Xq11.2-q21.1 (Therman et al. (1974, 1979); Mattei et al., 1981), Flejter et al. (1984) suggested that the highly specific bend is a visible manifestation of the condensation process. It may represent the first to be folded and the last to be unfolded portion of the inactive X. Continuing this work, Flejter et al. (1986) reasoned that the inactivation-associated fold might be useful for identifying the inactive X and locating the inactivation center in other mammalian species. They found that all 9 primate species examined expressed the fold. In most, the fold was at the band homologous to human Xq13-q21.

By study of inactivation of the X chromosome in somatic cell hybrids containing rearranged chromosomes, Brown and Willard (1989) regionalized the human X inactivation center, symbolized XIC by them, to Xq13. Brown et al. (1991) defined a minimal region of overlap of structurally abnormal X chromosomes capable of being inactivated. The results were consistent with models invoking a single XIC at chromosome Xq13. One of the markers localized to this region was the XIST gene, which is expressed specifically from inactive, but not active, X chromosomes.

Cytogenetic analyses show that the region Xq11.2-q21 is retained in all structurally abnormal X chromosomes. From such observations the conclusion is drawn that this 'critical region' contains the locus controlling X inactivation. Structurally abnormal X chromosomes without the X inactivation center would allow nullisomy, disomy, or trisomy for genes on the X chromosome--presumably nonviable states. Pettigrew et al. (1991) studied a 28-year-old woman with primary amenorrhea and features of Turner syndrome who had an isodicentric chromosome involving Xp. High resolution chromosome analysis showed that the break in the long arm was at Xq13.2. DNA analysis confirmed the breakpoint of the isodicentric chromosome to be proximal to PGK1, which is located at Xq13.

▼ Gene Function

Kay et al. (1993) showed that the onset of Xist expression in mouse development preceded X chromosome inactivation, suggesting that it may be a cause rather than merely a consequence of X inactivation. The earliest Xist expression in morulae and blastocysts was imprinted, resulting in specific expression of the paternal Xist allele. Thus, imprinting may be the cause of nonrandom inactivation of the paternal X in trophectoderm. The imprint on Xist expression was lost shortly before gastrulation, when random X inactivation occurs.

Consistent with the fact that the mouse Xist gene is expressed exclusively from the inactive X chromosome, Norris et al. (1994) showed that in somatic tissues the 5-prime end of the silent Xist allele on the active X chromosome was fully methylated, while the expressed allele on the inactive X was completely unmethylated. In tissues that undergo imprinted paternal Xist expression and imprinted X inactivation, the paternal Xist allele was unmethylated, and the silent maternal allele was fully methylated. In the male germline, a developmentally regulated demethylation of Xist occurred at the onset of meiosis and was retained in mature spermatozoa. This may be the cause of imprinted expression of the paternal Xist allele. A role for methylation in the control of Xist expression was further supported by the finding that in differentiating mouse embryonic stem cells during the initiation of X inactivation, differential methylation of Xist alleles preceded the onset of Xist expression.

Torchia et al. (1994) used FISH to examine the early versus late replication of loci on the X chromosome and the relationship between activity of the gene and late replication. Active autosomal genes tend to replicate early, whereas inactive ones are more permissive and frequently replicate later. In the assay used, an unreplicated locus was characterized by a single hybridization signal, and a replicated locus by a doublet hybridization signal. The percentage of doublets was used as a measure of relative time of replication in S phase. Torchia et al. (1994) concluded that silence of the XIST gene in males is associated with late replication of the locus, whereas the locus replicates asynchronously in the 2 X chromosomes in female cells. The expansion of the FMR1 locus (309550) in fragile X males (see 300624) led to late replication. The gene for factor VIII (300841) was late replicating in both normal and fragile X males and replicated at nearly the same time on active and inactive X chromosomes in females, consistent with inactivity of this gene in the tissue analyzed.

Hansen et al. (1995) presented data in direct opposition to the conclusion of Torchia et al. (1994). They demonstrated early replication of XIST on the active X and late replication on the inactive X in the same cell type, namely human fibroblasts. They believed that the discrepancy could be explained by the indirect nature of the FISH-based method, which is susceptible to errors because of the tendency of some loci not to separate after replication, thus appearing to be unduplicated, and for transcribed loci to yield false doublet (replicated) signals when genomic probes are used that hybridized to nascent transcripts (Hansen and Gartler, 1997).

The role of the Xist gene in X chromosome inactivation as the master regulatory switch locus was supported solely by indirect evidence until the experiments of Penny et al. (1996), who provided direct evidence by gene targeting of Xist in mouse embryonic stem (ES) cells. Their results provided evidence for the absolute requirement of Xist in the process of X chromosome inactivation. When ES cells that are chromosomally XX are maintained in the undifferentiated state, both X chromosomes remain active and Xist is expressed at very low levels; however, when they are allowed to differentiate, X inactivation occurred and Xist expression increased markedly. Penny et al. (1996) knocked out 7 kb of DNA, including the first Xist exon, and showed that this destroyed the activity of the gene. When ES cells heterozygous for distinguishable alleles of Xist and other X-linked genes were allowed to differentiate, X inactivation occurred, as manifested by an asynchronously replicating chromosome, but only the X not bearing the knockout underwent inactivation. Penny et al. (1996) concluded that the counting mechanism still recognized the XIC with the null Xist allele; that the normal or the knockout X could be selected to remain active with a probability, depending on the different Xce alleles they carried; that if the knockout X was selected to remain active, the other X underwent inactivation normally; but that if the normal X was selected, then the knockout X failed to become inactive and the cell then had 2 active X chromosomes. The authors also studied the effect of the Xist knockout in vivo in chimeric mouse embryos made by aggregating ES cells carrying the knockout with normal 8-cell embryos. Again, the counting mechanism operated and X inactivation occurred, and once more only the X with the normal Xist allele underwent inactivation. In contrast to the ES cells, there was no evidence of cells with both X chromosomes active, an observation consistent with earlier work showing that cells with excess X-chromosome activity are rapidly eliminated by cell selection. Thus, the work of Penny et al. (1996) provided clear evidence that transcription of Xist in mice is required for the spreading of inactivation along the X chromosome carrying it.

Lyon (1996) commented that the experiments of Penny et al. (1996) indicated that the counting and spreading functions of the XIC have to some extent been separated. She suggested that counting may be a later evolutionary development found only in eutherians. Lyon (1996) noted that spreading is a long range process apparently operative over megabases, but with some form of local response in that some genes escape inactivation. She also noted that in cells that have already undergone X inactivation, loss of the XIST gene does not cause reactivation. Thus, the significance of expression of XIST in adult tissues is unclear. Migeon et al. (1996) provided evidence of the separate counting mechanism in humans.

Lee and Lu (1999) created a targeted deletion of the Tsix gene (300181) in female and male mouse cells. Despite a deficiency of Tsix RNA, X-chromosome counting remained intact: female cells still inactivated 1 X, while male cells blocked X inactivation. However, heterozygous female cells showed skewed Xist expression and primary nonrandom inactivation of the mutant X. The ability of the mutant X to block Xist accumulation was compromised. The authors concluded that Tsix regulates Xist in cis and determines X-chromosome choice without affecting silencing. Therefore, counting, choice, and silencing are genetically separable. Contrasting effects in XX and XY cells argued that negative and positive factors are involved in choosing active and inactive X chromosomes.

During mouse preimplantation development, the exclusive expression of the Xist gene from the paternal inherited allele is thought to play a role in the inactivation of the paternally inherited X chromosome in the extraembryonic cell lineages of the developing female embryo. Preferential paternal X inactivation occurs in first-trimester human trophoblastic cells also (Goto et al., 1997), a situation that persists until birth when preferential paternal X inactivation is demonstrable in full-term placentas (Harrison, 1989). Daniels et al. (1997) determined whether the pattern of XIST expression in human preimplantation embryos is similarly correlated with paternal X inactivation. They developed procedures sensitive to a single cell, for the simultaneous analysis of XIST and HPRT expression and of sexing, initially using human fibroblast cells. Application of these procedures to human cleavage-stage embryos derived by in vitro fertilization revealed a pattern of XIST expression different from that in the mouse. Transcripts of the XIST gene were detected as early as the 1-cell zygote and, with increasing efficiency, through to the 8-cell stage of preimplantation development. In addition, transcripts of XIST were detected in both male (hence from the maternally inherited allele) and female preimplantation embryos. This pattern of expression is not consistent with a role for the early expression of XIST in the choice of paternal X inactivation in the extraembryonic cell lineages of the developing human embryo. Ray et al. (1997) likewise found expression of the XIST gene in human preimplantation embryos from the 5- to 10-cell stage onwards consistent with its role in the initiation of inactivation. They found also that, in contrast to the mouse, transcripts were detected in both male and female embryos demonstrating XIST expression from the maternally derived X chromosome in male embryos, X(M)Y. Brown and Robinson (1997) discussed this mouse/human paradox.

Panning et al. (1997) demonstrated that low-level Xist expression was detected from both active X chromosomes prior to X inactivation in female mouse ES cells. A similar low-level expression was detected from the single active X chromosome in male mouse ES cells. After differentiation, high-level Xist expression occurred only in the inactive X chromosome. Differentiating female cells increased Xist expression from the inactive X chromosome, prior to silencing low-level Xist expression on the active X. The transition from low-level to high-level Xist expression was achieved by stabilization of Xist transcripts at the inactive X. Panning et al. (1997) suggested that these developmentally modulated changes in Xist expression are regulated by several different mechanisms: factors that stabilize Xist transcripts at the inactive X, an activity that blocks the stabilization at the active X, and a mechanism that silences low-level Xist expression from the active X.

To understand transcriptional regulation of the XIST gene, Hendrich et al. (1997) identified and characterized the human XIST promoter and 2 repeated DNA elements that modulate promoter activity. As determined by reporter gene constructs, the XIST minimal promoter is constitutively active at high levels in human male and female cell lines and in transgenic mice. Promoter activity is dependent in vitro on the binding of the common transcription factors SP1 (189906), YY1 (600013), and TBP (600075). The authors further identified 2 cis-acting repeated DNA sequences that influence reporter gene activity. DNA fragments containing a set of highly conserved repeats located within the 5-prime end of XIST stimulated reporter activity 3-fold in transiently transfected cell lines. Additionally, a 450-bp alternating purine-pyrimidine repeat located 25 kb upstream of the XIST promoter partially suppressed promoter activity by approximately 70% in transient transfection assays. Hendrich et al. (1997) concluded that the XIST promoter is constitutively active and that critical steps in the X inactivation process must involve silencing of XIST on the active X chromosome by factors that interact with and/or recognize sequences located outside the minimal promoter.

To characterize functional elements in the Xist gene important to X chromosome inactivation, Clerc and Avner (1998) created a deletion extending 3-prime to exon 6 of mouse Xist. In undifferentiated mouse ES cells, Xist expression from the deleted X chromosome was markedly reduced. In differentiated XX mouse ES cells containing 1 deleted X chromosome, the X inactivation process still occurred but was never initiated from the unmutated X chromosome. In differentiated mouse ES cells that were essentially XO, the mutated Xic was capable of initiating X inactivation, even in the absence of another Xic. These results demonstrated a role for the region 3-prime to Xist exon 6 in the counting process and suggested that counting is mediated by a repressive mechanism that prevents inactivation of a single X chromosome in diploid cells. Carrel and Willard (1998) discussed the implications of the experiments of Clerc and Avner (1998) and presented with diagrams the 3 general models proposed for the initiation of X inactivation and the establishment of active and inactive X chromosomes.

Johnston et al. (1998) showed that alternate promoter usage of the murine Xist gene resulted in distinct stable and unstable RNA isoforms. Unstable Xist transcripts initiated at a novel upstream promoter (P0), whereas stable Xist RNA was transcribed from the previously identified promoter (P1) and from a novel downstream promoter (P2). Analysis of cells undergoing X inactivation indicated that a developmentally regulated promoter switch mediated stabilization and accumulation of Xist RNA on the inactive X chromosome.

To test the hypothesis of Johnston et al. (1998), Warshawsky et al. (1999) examined expression and half-life of Xist RNA produced from a mouse Xist transgene lacking P0 but retaining P1. They confirmed the previous finding that P0 is dispensable for Xist expression in undifferentiated cells and that P1 can be used in both undifferentiated and differentiated cells. They showed that Xist RNA initiated at P1 is unstable and does not accumulate. Further analysis indicated that the transcriptional boundary at P0 does not represent the 5-prime end of a distinct Xist isoform. Instead, P0 was an artifact of cross-amplification caused by a pseudogene of the highly expressed ribosomal protein S12 gene (RPS12; 603660). Using strand-specific techniques, they found that transcription upstream of P1 originates from the DNA strand opposite Xist and represents the 3-prime end of the antisense Tsix RNA (300181). Thus, their data did not support the existence of a P0 promoter and suggested that mechanisms other than switching of functionally distinct promoters control the upregulation of Xist.

Duthie et al. (1999) used FISH analysis to study the association of rodent Xist RNA with the inactive X chromosome at metaphase. Xist transcripts specifically localized to nonheterochromatin domains on the inactive X, in discrete banded pattern. Duthie et al. (1999) suggested that gaps in the Xist RNA banding pattern correlated with the location of late replicating, G-dark bands. Using X-autosome rearrangement, Duthie et al. (1999) demonstrated that Xist RNA associates more efficiently with X chromatin than with cis-linked autosomal material.

To study the initiation of X inactivation, Wutz and Jaenisch (2000) generated a full-length mouse Xist cDNA transgene and an inducible expression system facilitating controlled Xist expression in ES cells and differentiated cultures. In ES cells, transgenic Xist RNA was stable and caused long-range transcriptional repression in cis. Repression was reversible and dependent on continued Xist expression in ES cells and early ES cell differentiation. By 72 hours of differentiation, inactivation became irreversible and independent of Xist. Upon differentiation, autosomal transgenes did not effect counting, but transgenic Xist RNA induced late replication and histone H4 hypoacetylation. Xist had to be activated within 48 hours of differentiation to effect silencing, suggesting that reversible repression by Xist is a required initiation step that might occur during normal X inactivation in female cells.

Coating of the X chromosome by Xist RNA is an essential trigger for X inactivation in mice. Heard et al. (2001) reported that methylation of lys9 of histone H3 (see 602810) on the inactive mouse X chromosome occurred immediately after Xist RNA coating and before transcriptional inactivation of X-linked genes. X-chromosomal H3-lys9 methylation occurs during the same window of time as H3-lys9 hypoacetylation and H3-lys4 hypomethylation. Histone H3 modifications thus represent the earliest known chromatin changes during X inactivation. The authors also identified a unique 'hotspot' of H3-lys9 methylation 5-prime to Xist and proposed that this acts as a nucleation center for Xist RNA-dependent spread of inactivation along the X chromosome via H3-lys9 methylation.

Gartler and Riggs (1983) put forth the concept of 'booster' elements or 'way stations,' which were concentrated at the X-inactivation center and at other positions throughout the X chromosome. In their model, expanded upon by Riggs (1990), the unique organization of these elements served to amplify and spread the X-inactivation signal along the entire length of the chromosome. Lyon (1998) proposed long interspersed repeat element-1, or L1 (e.g., 151626), as a candidate for these 'booster' elements. L1 elements are mammal-specific retrotransposons with active members in the human genome. The Lyon 'repeat hypothesis' was based largely on 2 observations. First, FISH studies in human and mouse using L1 repeat elements as probes showed that the X chromosome of each species hybridized more intensely than autosomes and was therefore presumably enriched for these elements. Second, her reexamination of mouse X-autosome translocation data showed that failure of the X-inactivation signal to spread often correlated with cytogenetic bands that were deficient in L1 elements.

Using data collected from the Human Genome Project, Bailey et al. (2000) sought to investigate more precisely the pattern of L1 distribution along the X chromosome, to compare this pattern to its distribution in human autosomes, and to determine whether its nonrandom organization was consistent with the known biology of X inactivation. They presented data indicating that the L1 composition of the human X chromosome is fundamentally distinct from that of human autosomes. The human X chromosome is enriched 2-fold for L1 repetitive elements, with the greatest enrichment observed for a restricted subset of L1 elements that were active less than 100 million years ago. Regional analysis of the X chromosome showed that the most significant clustering of these elements is in Xq13-q21 (the center of X inactivation). Genomic segments harboring genes that escape inactivation are significantly reduced in L1 content compared with X chromosome segments containing genes subject to X inactivation, providing further support for the association between X inactivation and L1 content. These nonrandom properties of L1 distribution on the X chromosome provided strong evidence that L1 elements may serve as DNA signals to propagate X inactivation along the chromosome.

Eggan et al. (2000) studied X inactivation in cloned mouse embryos. Both X chromosomes were active during cleavage of cloned embryos, followed by random X inactivation in the embryo proper. In the trophectoderm, X inactivation was nonrandom, with the inactivated X of the somatic donor being chosen for inactivation. When female embryonic stem cells with 2 active X chromosomes were used as donors, random X inactivation was seen in trophectoderm and embryo. Eggan et al. (2000) concluded that these results demonstrated that epigenetic marks can be removed and reestablished on either X chromosome during cloning, and that the epigenetic marks imposed on the X chromosomes during gametogenesis are functionally equivalent to the marks imposed on the chromosomes during somatic X inactivation.

Matsui et al. (2001) used RNA fluorescence in situ hybridization in parthenogenetic embryos to study the control of Xist/Tsix expression for silencing the entire X chromosome in mice. The paternally derived Xist allele was highly expressed in every cell of the embryo from the 4-cell stage onward, irrespective of the number of X chromosomes in a diploid cell. The high level of Xist transcription was maintained in nonepiblast cells culminating in Xp (paternal X) inactivation, whereas in Xp0 (lacking a paternal X) embryos it was terminated by the blastocyst stage, probably as a result of counting the number of X chromosomes in a cell occurring at the morula/blastocyst stage. Xist was also downregulated in epiblast cells of XmXp and XmXmXp embryos to make X inactivation random. In epiblast cells, Xist seemed to be upregulated after counting and random choice of the future inactive X chromosome(s). Although the maternal Xist allele was never activated in fertilized embryos before implantation, some parthenogenetic embryos showed Xist upregulation in a proportion of cells. Matsui et al. (2001) suggested that imprinted X inactivation in nonepiblast tissues of rodents may be derived from the random X-inactivation system.

Using male and female mouse dermal fibroblasts and peptide nucleic acid-interference mapping, Beletskii et al. (2001) characterized Xist binding and X inactivation. They determined that a single 19-bp sequence complementary to a distinct repeat region in the first exon of Xist completely abolished binding of Xist to the X chromosome and prevented X inactivation. The association of the inactivated X chromosome with macrohistone H2a (see 613499) was also disturbed by introduction of the inhibitory sequence.

Chao et al. (2002) identified the insulator and transcription factor Ctcf (604167) as a candidate trans-acting factor for X chromosome selection in mouse. The choice/imprinting center contains tandem Ctcf-binding sites that function in an enhancer-blocking assay. In vitro binding is reduced by CpG methylation and abolished by including non-CpG methylation. Chao et al. (2002) postulated that Tsix and Ctcf together establish a regulatable epigenetic switch for X inactivation. Murine Tsix contains greater than 40 Ctcf motifs, and the human sequence has greater than 10.

Hall et al. (2002) investigated 4 adult male HT-1080 fibrosarcoma cell lines expressing ectopic human XIST and demonstrated that these postdifferentiation cells can undergo chromosomal inactivation outside of any normal developmental context. All 4 clonal lines inactivated the transgene-containing autosome to varying degrees and with variable stability. The results suggested that some postdifferentiation cell lines are capable of de novo chromosomal inactivation; however, long-term retention of autosomal inactivation was less common, suggesting that autosomal inactivation may confer a selective disadvantage.

Ganesan et al. (2002) found that BRCA1 (113705) colocalized with markers of the inactive X chromosome (Xi) on Xi in female somatic cells and associated with XIST RNA, as detected by chromatin immunoprecipitation. Breast and ovarian carcinoma cells lacking BRCA1 showed evidence of defects in Xi chromatin structure. Reconstitution of BRCA1-deficient cells with wildtype BRCA1 led to the appearance of focal XIST RNA staining without altering XIST abundance. Inhibiting BRCA1 synthesis in a suitable reporter line led to increased expression of an otherwise silenced Xi-located GFP transgene. These observations suggested that loss of BRCA1 in female cells may lead to Xi perturbation and destabilization of its silenced state.

To elucidate which Xist RNA sequences are necessary for chromosomal association and silencing, Wutz et al. (2002) used an inducible Xist expression system in mouse embryonic stem cells that recapitulates long-range chromosomal silencing. They showed that chromosomal association and spreading of Xist RNA can be functionally separated from silencing by specific mutations. Silencing requires a conserved repeat sequence located at the 5-prime end of Xist. Deletion of this element results in Xist RNA that still associates with chromatin and spreads over the chromosome but does not effect transcriptional repression. Association of Xist RNA with chromatin is mediated by functionally redundant sequences that act cooperatively and are dispersed throughout the remainder of Xist but show little or no homology.

Huynh and Lee (2003) found that in mice, one X chromosome is already silent at zygotic gene activation (2-cell stage). This X chromosome is paternal in origin and exhibits a gradient of silencing. Genes close to the X inactivation center show the greatest degree of inactivation, whereas more distal genes show variable inactivation and can partially escape silencing. After implantation, imprinted silencing in extraembryonic tissues becomes globalized and more complete on a gene-by-gene basis. Huynh and Lee (2003) suggested that their results argue that the XX embryo is in fact dosage compensated at conception along much of the X chromosome, and proposed that imprinted X inactivation results from inheritance of a preinactivated X chromosome from the paternal germline.

Plath et al. (2003) demonstrated that transient recruitment of the Eed (605984)-Ezh2 (601573) complex to the inactive X chromosome occurred during initiation of X inactivation in both extraembryonic and embryonic mouse cells and was accompanied by methylation of histone H3 at lys27 (H3-K27). Recruitment of the complex and methylation on the inactive X depended on Xist RNA but were independent of its silencing function. Plath et al. (2003) concluded that taken together, their results suggest a role for Eed-Ezh2-mediated H3-K27 methylation during initiation of both imprinted and random X inactivation and demonstrate that H3-K27 methylation is not sufficient for silencing of the inactive X.

By PCR analysis, Chow et al. (2003) identified a truncated XIST transcript that was expressed in human female somatic cells and in human male N-Tera2D1 pluripotent embryonal carcinoma cells at a much lower level. N-Tera2D1 cells, but not male or female human somatic cells, also expressed an antisense transcript at about the same level as the truncated XIST transcript. The half-life of XIST in N-Tera2D1 cells was approximately the same as that of XIST in female somatic cells, suggesting that the antisense transcript does not regulate XIST stability. Female somatic cells, but not N-Tera2D1 or male somatic cells, expressed a downstream antisense transcript that did not overlap with the 3-prime exons of XIST, but localized to nuclei with XIST. The ENOX gene (NCRNA00183; 300832), which is located about 90 kb upstream of XIST, was expressed from both the active and inactive X chromosome in somatic cell hybrids, thus delimiting the extent of silencing on the active X chromosome.

In independent studies, Mak et al. (2004) and Okamoto et al. (2004) found that although initially active, the paternal X chromosome undergoes imprinted inactivation from the cleavage stages, well before cellular differentiation. A reversal of the inactive state, with a loss of epigenetic marks such as histone modifications and polycomb proteins, subsequently occurs in cells of the inner cell mass (ICM), which give rise to the embryo proper in which random X inactivation is known to occur. Okamoto et al. (2004) concluded that their observations reveal the remarkable plasticity of the X-inactivation process during preimplantation development of mice and underlines the importance of the ICM in global reprogramming of epigenetic marks in the early embryo.

Okamoto et al. (2005) showed that Xist transgenes, located on autosomes, did not undergo meiotic sex chromosome inactivation (MSCI) in the male germ line of mice and yet could induce imprinted cis-inactivation when paternally inherited, with identical kinetics to the Xp chromosome. Okamoto et al. (2005) suggested that MSCI is not necessary for imprinted X chromosome inactivation in mice. They also demonstrated that the Xp is transcribed, like autosomes, at zygotic gene activation rather than being 'preinactivated.' Okamoto et al. (2005) proposed that expression of the paternal Xist gene at zygotic gene activation is sufficient to trigger cis-inactivation of the X chromosome, or of an autosome carrying a Xist transgene.

Ma and Strauss (2005) studied the short (S) and long (L) forms of mouse Xist RNA, which differ in their 3-prime ends. They identified a single S variant that was posttranscriptionally polyadenylated, but it differed from other polyadenylated RNAs in that the conserved hexamer signal sequence was 130 nucleotides, rather than 10 to 30 nucleotides, upstream of the cleavage/adenylation site, and the penultimate base to the cleavage site was guanine rather than cytosine. Ma and Strauss (2005) identified several L variants. None were polyadenylated, but some contained a genomically encoded adenine stretch. One form had a string of 5 adenines, another had 10, and others had no 3-prime adenines. As expected, no Xist expression was detected in embryoid bodies derived from male ES cells. A single L variant with an adenine stretch predominated in embryoid bodies derived from female ES cells, and only small amounts of the S form were associated with female embryoid bodies. Thus, in preimplantation embryos, the majority of Xist transcript was the L form. In adult female brain, kidney, liver, heart, spleen, lung, and muscle, the L and S forms were present in similar amounts. There appeared to be 5 different types of the L transcript in adult female somatic tissue.

Xu et al. (2006) showed that in mouse embryonic stem cells interchromosomal pairing mediates communication between X chromosomes to regulate X inactivation and ensure mutually exclusive silencing. Pairing occurs transiently at the onset of X inactivation and is specific to the X inactivation center. Deleting Xite (300074) and Tsix (300181) perturbed pairing and counting/choice, whereas their autosomal insertion induced de novo X-autosome pairing. Ectopic X-autosome interactions inhibited endogenous X-X pairing and blocked the initiation of X-chromosome inactivation. Thus, Tsix and Xite function both in cis and in trans. Xu et al. (2006) proposed that Tsix and Xite regulate counting and mutually exclusive choice through X-X pairing.

Using 3-dimensional fluorescence in situ hybridization analysis, Bacher et al. (2006) showed that the 2 X inactivation centers (Xics) transiently colocalized, just before X inactivation, in differentiating mouse female embryonic stem cells. Using Xic transgenes capable of imprinted but not random X inactivation, and Xic deletions that disrupt random X inactivation, Bacher et al. (2006) demonstrated that Xic colocalization was linked to Xic function in random X inactivation. Both long-range sequences and the Tsix element, which generates the antisense transcript to Xist, were required for transient interaction of Xics. Bacher et al. (2006) proposed that transient colocalization of Xics may be necessary for a cell to determine Xic number and to ensure the correct initiation of X inactivation.

Augui et al. (2007) found that a segment of the mouse Xic lying several hundred kilobases upstream of Xist brought the 2 Xics together before the onset of X inactivation. This region could autonomously drive Xic trans-interactions even as an ectopic single-copy transgene. Its introduction into male embryonic stem cells was strongly selected against, consistent with a possible role in trans-activating Xist. Augui et al. (2007) proposed that homologous associations driven by this novel X-pairing region of the Xic enable a cell to sense that more than 1 X chromosome is present and coordinate reciprocal Xist/Tsix expression.

Chow et al. (2007) used an inducible system to ectopically express XIST in human cell lines. XIST integrated into chromosome 3 in male HT1080 fibrosarcoma cells. XIST formed large nuclear foci upon induction, but it did not coat the entire chromosome. XIST expression coincided with loss of activated histone marks and repressed expression of a reporter gene, but there was no accumulation of repressive H3K9 or H3K27 methylation. Mutation analysis revealed that, consistent with mouse, only the 5-prime 10 kb of XIST were required for XIST localization and silencing. However, unlike mouse, where deletion of the A repeat within this 5-prime region abrogated gene silencing but not Xist accumulation, deletion of the A repeat in human XIST resulted in loss of both gene silencing and XIST accumulation. Chow et al. (2007) concluded that mouse and human XIST show some differentiating features and that accumulation of repressive histone marks is not required for XIST-dependent gene silencing in human cells.

Ogawa et al. (2008) reported that murine Xist and Tsix formed duplexes in vivo. During X chromosome inactivation, the duplexes were processed to small RNAs, most likely on the active X chromosome in a Dicer (606241)-dependent manner. Deleting Dicer compromised small RNA production and derepressed Xist. Furthermore, without Dicer, Xist RNA could not accumulate and histone H3 lysine-27 trimethylation was blocked in the inactive X. These defects were partially rescued by truncating Tsix. Thus, Ogawa et al. (2008) concluded that X chromosome inactivation and RNA interference intersect, downregulating Xist on the active X chromosome and spreading silencing on the inactive X chromosome.

During mouse embryogenesis, reversion of imprinted X chromosome inactivation in the pluripotent inner cell mass of the female blastocyst is initiated by the repression of Xist from the paternal X chromosome. Navarro et al. (2008) reported that key factors supporting pluripotency--Nanog (607937), Oct3/4 (164177), and Sox2 (184429)--bound within Xist intron 1 in undifferentiated ES cells. Whereas Nanog-null ES cells displayed a reversible and moderate upregulation of Xist in the absence of any apparent modification of Oct3/4 and Sox2 binding, the drastic release of all 3 factors from Xist intron 1 triggered rapid ectopic accumulation of Xist RNA. Navarro et al. (2008) concluded that the 3 main genetic factors underlying pluripotency cooperate to repress Xist and thus couple X inactivation reprogramming to the control of pluripotency during embryogenesis in the mouse.

Van den Berg et al. (2009) used cryopreserved and surplus embryos from in vitro fertilization treatments to study X inactivation in preimplantation human embryos. Female embryos showed punctate FISH staining for XIST at the 8-cell stage, and the signal gradually accumulated on 1 of the X chromosomes at the late morula and blastocyst stages. A few male embryos showed brief punctate XIST staining only at the morula stage. The area of the X chromosome that was at least partially coated with XIST was transcriptionally silent, demonstrating that X inactivation and dosage compensation commences in preimplantation female human embryos. Human cumulus cells, amniocytes, and preimplantation blastocysts had Barr bodies that were positive for macroH2A and trimethylated H3K27, showing that once XIST coats the X chromosome, epigenetic changes are induced that lead to X chromosome inactivation. The order of these changes was similar to that observed in mouse preimplantation embryos and ES cells, although XIST expression occurred later in humans than in mice, corresponding to the time of embryonic genome activation in each species.

In mice, the paternal X chromosome is silenced during early embryogenesis owing to imprinted expression of Xist. Paternal X chromosome inactivation (XCI) is reversed in the inner cell mass of the blastocyst, and random XCI subsequently occurs in epiblast cells. Okamoto et al. (2011) showed that other eutherian mammals have very different strategies for initiating XCI. In rabbits and humans, the Xist homolog is not subject to imprinting, and XCI begins later than in mice. Furthermore, Xist is upregulated on both X chromosomes in a high proportion of rabbit and human embryo cells, even in the inner cell mass. In rabbits, this triggers XCI on both X chromosomes in some cells. In humans, chromosomewide XCI has not initiated even by the blastocyst stage, despite the upregulation of XIST. The choice of which X chromosome will finally become inactive thus occurs downstream of Xist upregulation in both rabbits and humans, unlike in mice. Okamoto et al. (2011) concluded that their study demonstrated the remarkable diversity in XCI regulation and highlighted differences between mammals in their requirement for dosage compensation during early embryogenesis.

Using female mouse embryonic fibroblasts, Jeon and Lee (2011) discovered that Xist required Yy1 for its localization and accumulation on Xi. Knockdown of Yy1 resulted in diffusion of Xist away from Xi, but did not result in Xist degradation. Jeon and Lee (2011) determined that Yy1 anchored Xist to DNA by binding different nucleic acid motifs in the Xist gene and Xist RNA. In the Xist gene, a cluster of Yy1-binding sites corresponded to the nucleation center for Xist binding and X inactivation. In Xist RNA, Yy1 bound a conserved C-rich element that is repeated 14 times. Jeon and Lee (2011) concluded that YY1 is a multifunction protein critical for docking of Xist to Xi.

Gontan et al. (2012) identified the pluripotency factor REX1 (614572) as a key target of RNF12 (300379) in the mechanism of X-chromosome inactivation. Mouse Rnf12 caused ubiquitination and proteasomal degradation of Rex1, and Rnf12-knockout mouse embryonic stem cells showed an increased level of Rex1. Using chromatin immunoprecipitation sequencing, Rex1-binding sites were detected in mouse Xist and Tsix regulatory regions. Overexpression of Rex1 in female embryonic stem cells inhibited Xist transcription and X-chromosome inactivation, whereas male Rex1 +/- embryonic stem cells showed ectopic X-chromosome inactivation. From this, Gontan et al. (2012) proposed that RNF12 causes REX1 breakdown through dose-dependent catalysis, thereby representing an important pathway to initiate X-chromosome inactivation. REX1 and XIST are present only in placental mammals, which points to coevolution of these 2 genes and X-chromosome inactivation.

Jiang et al. (2013) tested the concept that a gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, XIST. Using genome editing with zinc finger nucleases, Jiang et al. (2013) inserted a large inducible XIST transgene into the DYRK1A (600855) locus on chromosome 21 in Down syndrome (190685) pluripotent stem cells. The XIST noncoding RNA coats chromosome 21 and triggers stable heterochromatin modifications, chromosomewide transcriptional silencing, and DNA methylation to form a 'chromosome 21 Barr body.' This provided a model to study human chromosome inactivation and created a system to investigate genomic expression changes and cellular pathologies of trisomy 21, free from genetic and epigenetic noise. Notably, deficits in proliferation and neural rosette formation are rapidly reversed upon silencing 1 chromosome 21. Jiang et al. (2013) suggested that their successful trisomy silencing in vitro surmounted the major first step towards potential development of chromosome therapy.

Engreitz et al. (2013) investigated the localization mechanisms of the Xist LncRNA during X-chromosome inactivation (XCI), a paradigm of LncRNA-mediated chromatin regulation. During the maintenance of XCI, Xist binds broadly across the X chromosome. During initiation of XCI, Xist initially transfers to distal regions across the X chromosome that are not defined by specific sequences. Instead, Xist identifies these regions by exploiting the 3-dimensional conformation of the X chromosome. Xist requires its silencing domain to spread across actively transcribed regions and thereby access the entire chromosome. Engreitz et al. (2013) concluded that their findings suggested a model in which Xist coats the X chromosome by searching in 3 dimensions, modifying chromosome structure, and spreading to newly accessible locations.

Simon et al. (2013) generated high-resolution maps of XIST binding on the X chromosome across a developmental time course using CHART-seq (capture hybridization analysis of RNA targets with deep sequencing). In female cells undergoing XCI de novo, XIST follows a 2-step mechanism, initially targeting gene-rich islands before spreading to intervening gene-poor domains. XIST is depleted from genes that escape XCI but may concentrate near escapee boundaries. XIST binding is linearly proportional to Polycomb repressive complex-2 (PRC2; see 601674) density and H3K27me3, indicating comigration of XIST and PRC2. Interestingly, when XIST is acutely stripped from the inactive X in post-XCI cells, XIST recovers quickly within both gene-rich and gene-poor domains on a timescale of hours instead of days, indicating a previously primed inactive X chromatin state. Simon et al. (2013) concluded that XIST spreading takes distinct stage-specific forms. During initial establishment, XIST follows a 2-step mechanism, but during maintenance, XIST spreads rapidly to both gene-rich and gene-poor regions.

Using quantitative mass spectrometry, McHugh et al. (2015) developed a method to purify a lncRNA from cells and to identify proteins interacting with it directly. The authors identified 10 proteins that specifically associate with XIST, 3 of which, SHARP (613484), SAFA (602869), and LBR (600024), are required for XIST-mediated transcriptional silencing. McHugh et al. (2015) showed that SHARP, which interacts with the SMRT (600848) corepressor that activates HDAC3 (605166), is not only essential for silencing, but is also required for the exclusion of POLR2 (180660) from the inactive X. Both SMRT and HDAC3 are also required for silencing and POLR2 exclusion. In addition to silencing transcription, SHARP and HDAC3 are required for XIST-mediated recruitment of PRC2 across the X chromosome. McHugh et al. (2015) concluded that XIST silences transcription by directly interacting with SHARP, recruiting SMRT, activating HDAC3, and deacetylating histones to exclude POLR2 across the X chromosome.

Chen et al. (2016) showed that Xist directly interacts with the lamin B receptor (LBR), an integral component of the nuclear lamina, and that this interaction is required for Xist-mediated silencing by recruiting the inactive X to the nuclear lamina, which enables Xist to spread to actively transcribed genes across the X. Chen et al. (2016) concluded that lamina recruitment changes the 3D structure of DNA, enabling Xist and its silencing proteins to spread across the X to silence transcription. Wang et al. (2017) stated that their analysis indicated that a deletion of an LBR binding site in Xist, introduced by Chen et al. (2016) to study the effect of Xist-LBR interaction on Xist-mediated transcriptional silencing, was in fact an inversion, and that therefore the conclusions reached by Chen et al. (2016) were not valid. Chen et al. (2017) replied that the cells used in the experiments did contain a proper deletion, that the confusion was caused by DNA probes used in the experiment, and that their conclusions would not have been altered in any case.

Minajigi et al. (2015) developed and RNA centric proteomic method called iDRiP (identification of direct RNA interacting proteins). Using iDRiP, they identified 80 to 200 proteins in the Xist interactome. The interactors fell into several functional categories including cohesions, condensins, topoisomerases, RNA helicases, chromatin remodelers, histone modifiers, DNA methyltransferases, nucleoskeletal factors, and nuclear matrix proteins. The authors found that while Xist attracts repressive complexes to the inactive X, it actively repels chromosomal architectural factors such as the cohesins from the inactive X. The authors found that in wildtype cells the active X is characterized by about 112 topologically associated domains and the inactive X by 2 megadomains. The authors also found that stability of the inactive X can be perturbed by targeted inhibition of multiple components of the Xist interactome.

Patil et al. (2016) demonstrated that, in human cells, XIST is highly methylated with at least 78 N6-methyladenosine (m6A) residues. No function for m6A in long noncoding RNAs had been demonstrated. Patil et al. (2016) showed that m6A formation in XIST, as well as in cellular mRNAs, is mediated by RNA-binding motif protein-15 (RBM15; 606077) and its paralog RBM15B (612602), which bind the m6A-methylation complex and recruit it to specific sites in RNA. This results in the methylation of adenosine nucleotides in adjacent m6A consensus motifs. Furthermore, Patil et al. (2016) showed that knockdown of RBM15 and RBM15B, or knockdown of METTL3 (612472), an m6A methyltransferase, impairs XIST-mediated gene silencing. A systematic comparison of m6A-binding proteins shows that YTHDC1 preferentially recognizes m6A residues on XIST and is required for XIST function. Additionally, artificial tethering of YTHDC1 to XIST rescues XIST-mediated silencing upon loss of m6A. These data revealed a pathway of m6A formation and recognition required for XIST-mediated transcriptional repression.

Dossin et al. (2020) showed in mice that Spen (613484) is a key orchestrator of XCI in vivo and elucidated its mechanism of action by showing that Spen is essential for initiating gene silencing on the X chromosome in preimplantation mouse embryos and in embryonic stem cells. Spen is dispensable for maintenance of XCI in neural progenitors, although it significantly decreases the expression of genes that escape XCI. The authors showed that Spen is immediately recruited to the X chromosome upon the upregulation of Xist, and is targeted to enhancers and promoters of active genes. Spen rapidly disengages from chromatin upon gene silencing, suggesting that active transcription is required to tether Spen to chromatin. Dossin et al. (2020) defined the SPOC domain as a major effector of the gene silencing function of Spen, and showed that tethering SPOC to Xist RNA is sufficient to mediate gene silencing. Dossin et al. (2020) identified the protein partners of SPOC, including NCoR (600849)/SMRT (600848), the m6A RNA methylation machinery, the NuRD complex (see MTA1, 603526), RNA polymerase II (see 180660), and factors involved in the regulation of transcription initiation and elongation. Dossin et al. (2020) proposed that SPEN acts as a molecular integrator for the initiation of XCI, bridging XIST RNA with the transcription machinery, as well as with nucleosome remodelers and histone deacetylases, at active enhancers and promoters.

Using mouse ES cells, Pandya-Jones et al. (2020) showed that the Xist RNA-binding proteins Ptbp19 (600693), Matr3 (164015), Tdp43 (TARDBP; 605078), and Celf1 (601074) assembled on the multivalent E-repeat element of Xist and, via self-aggregation and heterotypic protein-protein interactions, formed a condensate in the Xi. This condensate was required for gene silencing and for anchoring of Xist to the Xi territory and could be sustained in the absence of Xist. The E-repeat-binding proteins became essential coincident with transition to the Xist-independent XCI phase, indicating that the condensate seeded by the E-repeat underlies the developmental switch from Xist dependence to independence. Pandya-Jones et al. (2020) concluded that XIST forms the Xi compartment by seeding a heteromeric condensate consisting of ubiquitous RNA-binding proteins, revealing a novel mechanism for heritable gene silencing.

Reviews

Willard (1996) gave a review of the X inactivation center and the role of XIST in X chromosome inactivation.

Boumil and Lee (2001) reviewed the roles of Xist and Tsix in X inactivation.

In their review on the evolution of Xi in mammals, Romito and Rougeulle (2011) noted several differences in the control of XIST expression in humans and mouse, including the structural and regulatory relationship between XIST and TSIX and differential XIST imprinting.

▼ Molecular Genetics

Familial Skewed X Inactivation

Although it is commonly believed that the initiation of X inactivation is random, with an equal probability (50:50) that either X chromosome will be the inactive X in a given cell, significant variation in the proportion of cells with either X inactive is observed both in mice heterozygous for alleles at the Xce locus and among normal human females in the population; see familial skewed X inactivation (300087). Families in which multiple females demonstrate extremely skewed inactivation patterns that are otherwise quite rare in the general population are thought to reflect possible genetic influences on the X inactivation process. Plenge et al. (1997) reported a rare C-to-G transversion mutation (314670.0001) in the XIST minimal promoter that underlay both epigenetic and functional differences between the two X chromosomes in 9 females from 2 unrelated families. All females demonstrated preferential inactivation of the X chromosome carrying the mutation, suggesting that there is an association between alterations in the regulation of XIST expression and X chromosome inactivation. Migeon (1998) noted that the skewing of inactivation in these individuals ranged from extreme to minimal or no skewing. Furthermore, some individuals in both pedigrees showed skewing in the absence of the XIST mutation.

To confirm the association between the -43C-G mutation and skewed X inactivation, Pereira and Zatz (1999) analyzed this mutation in the XIST gene in a sample of women, all with skewed X-inactivation patterns in blood ranging from 80:20 to 100:0. These women, 32 Duchenne/Becker (DMD/BMD) muscular dystrophy carriers and 34 normal women controls, were selected from a large sample assessed for X-inactivation status (Sumita et al., 1998). Among the DMD/BMD carriers, 2 had clinical signs of muscular dystrophy. None of the 66 analyzed females had the -43C-G mutation.

Pugacheva et al. (2005) noted that the familial -43C-G mutation in the XIST promoter results in skewing of X chromosome inactivation towards the inactive X chromosome of heterozygous females, whereas a -43C-A mutation found primarily in the active X chromosome results in the opposite skewing pattern. Both mutations point to the existence of a factor that might be responsible for the skewed patterns. Pugacheva et al. (2005) identified this factor as CTCF (604167). They found that the mouse and human XIST promoters contain 1 homologous CTCF-binding sequence with the matching dG-contacts, which in human XIST includes the -43 position within the DNase I footprint of CTCF. While the -43C-A mutation abrogated CTCF binding, the -43C-G mutation resulted in a dramatic increase in CTCF-binding efficiency by altering the zinc finger-usage mode required for recognition of the altered dG-contacts of the mutant site. Thus, the skewing effect of the -43C-G and -43C-A mutations correlated with their effect on CTCF binding.

▼ Cytogenetics

Ring X Chromosomes

The severe phenotype of human females whose karyotype includes tiny ring X chromosomes has been attributed to the inability of the small ring X chromosome to inactivate. Migeon et al. (1993) provided compelling evidence in support of this suggestion. Using PCR, Southern blot analysis, and in situ hybridization, they looked for the presence of the XIST locus in tiny ring X chromosomes from 8 females who had multiple congenital malformations and severe mental retardation. They found that some rings lacked the XIST locus, while others had sequences homologous to probes for XIST; however, in the latter group, the locus was either not expressed or negligibly expressed, based on reverse transcription-PCR analysis. As XIST transcription is an indicator of X chromosome inactivity, the absence of XIST transcription strongly suggested that tiny ring X chromosomes in females with severe phenotypes are mutants in the X chromosome inactivation pathway and that the inability of these rings to inactivate is responsible for the severe phenotypes (Migeon et al., 1994). They recorded that they found that 3 X-linked loci (AR, 313700; TIMP, 305370; and PHKA1, 311870) were expressed in the ring chromosomes from 2 subjects, indicating that these chromosomes were indeed active. In addition, rings had active chromatin (as indicated by labeling with acetylated histone H4). This was taken as clear evidence that these rings represent chromosomal mutations affecting cis inactivation and that the severe phenotype is due to functional disomy resulting from lack of dosage compensation for genes present within the ring chromosome. Two other subjects had the XIST coding sequences present in the ring chromosome, suggesting that XIST coding sequences alone may not be sufficient for X inactivation. Breakpoints in formation of these ring chromosomes may have disrupted neighboring regulatory or enhancer sequences, or there may be a second gene in the XIC region essential for XIST transcription.

Turner et al. (2000) studied 47 females with a 45,X/46,r(X) karyotype and found 7 to have an XIST-negative ring. Only 1 of the 7 patients had the severe phenotype. The remaining 6 patients had physical phenotypes consistent with Turner syndrome. Turner et al. (2000) proposed explanations both for the severe phenotype and for the unexpectedly mild phenotypes in 6 patients.

▼ Evolution

Duret et al. (2006) showed that Xist evolved, at least partly, from a protein-coding gene and that the loss of protein-coding function of the proto-Xist coincided with the 4 flanking protein genes becoming pseudogenes. This event occurred after the divergence between eutherians and marsupials, suggesting that mechanisms of dosage compensation evolved independently in both lineages.

▼ Animal Model

To investigate the function of the Xist gene product, Marahrens et al. (1997) generated male and female mice that carried a deletion in the structural gene but maintained a functional Xist promoter. They found that males with the mutated allele developed normally and were fertile. Females who inherited the mutant gene from their mothers also developed normally, with the wildtype paternal X being exclusively inactivated in every cell. However, female mice inheriting the mutant Xist allele on the paternal X chromosome were severely growth-retarded and died early in embryogenesis. The wildtype maternal X chromosome was inactive in every cell of the growth-retarded embryo proper, whereas both chromosomes were expressed in the mutant female trophoblast where X inactivation is imprinted. However, an XO mouse with a paternally inherited Xist mutation was healthy and appeared normal. Marahrens et al. (1997) concluded that the imprinted lethal phenotype of the mutant females was due to the inability of extraembryonic tissue with 2 active X chromosomes to sustain the embryo. The results indicated that Xist RNA is required for female dosage compensation but plays no role in spermatogenesis. In a review of Xist, Solter and Wei (1997) commented: 'After reading the paper by Marahrens and colleagues, it becomes even more obvious that despite the tremendous progress made in the field over the last few years, the problem of X inactivation in mammals remains as complex and tantalizing as ever.'

Marahrens et al. (1998) created laboratory mice with targeted disruption of the Xist gene. Females heterozygous for an internal deletion in the Xist gene, which included part of exon 1 and extended to exon 5, underwent primary nonrandom inactivation of the wildtype X chromosome. The authors concluded that the Xist gene not only has a role in chromatin remodeling, but also includes an element required for the choice of which X chromosome to inactivate. In conflict with the prevailing view of how choosing occurs, the element identified by the deletion plays a positive role in the choice mechanism.

Kalantry et al. (2009) tested whether imprinted X chromosome inactivation, which results in preferential inactivation of the paternal X chromosome, occurs in mouse embryos inheriting an Xp lacking Xist. The authors found that silencing of Xp-linked genes can initiate in the absence of paternal Xist; Xist is, however, required to stabilize silencing along the paternal X chromosome. Xp-linked gene silencing associated with mouse imprinted X chromosome inactivation, therefore, can initiate in the embryo independently of Xist RNA.

Xist is not found in metatherians (marsupials), and how X-chromosome inactivation is initiated in these mammals had been the subject of speculation. Using the marsupial Monodelphis domestica, Grant et al. (2012) identified Rsx (RNA on the silent X), an RNA that has properties consistent with a role in X-chromosome inactivation. Rsx is a large, repeat-rich RNA that is expressed only in females and is transcribed from, and coats, the inactive X chromosome. In female germ cells, in which both X chromosomes are active, Rsx is silenced, linking Rsx expression to X-chromosome inactivation and reactivation. Integration of an Rsx transgene on an autosome in mouse embryonic stem cells leads to gene silencing in cis. Grant et al. (2012) concluded that their findings permitted comparative studies of X-chromosome inactivation in mammals and raised questions about the mechanisms by which X-chromosome inactivation is achieved in eutherians.

Dou et al. (2024) found that transgenic expression of female-specific Xist in male mice did not lead to manifestation of autoimmunity when a mouse strain was autoimmune resistant, indicating that Xist expression alone did not bypass the genetic barrier in mice. However, transgenic expression of Xist at least changed the T-cell profiles of males to that of females expressing Xist. When transgenic Xist was induced in an autoimmune-prone mouse strain, Xist expression in males induced autoantibodies and autoimmune pathology to female-level severity in males. Moreover, diseased male mice had distinct cell-type clustering and consistent reformatting of the chromatin landscape, and their T- and B-cell populations were reprogrammed to female-like patterns. Microarray analysis showed that multiple proteins from the XIST ribonucleoprotein (RNP) complex were autoantigens in patients with autoimmune disease, which was also seen in autoimmune-prone mice expressing Xist, indicating a role for the XIST RNP in the development of sex-biased autoimmune diseases.

▼ Nomenclature

XIC, for 'X inactivation center,' refers to a region on the X chromosome. XIST refers to a specific gene within that region that is necessary for X inactivation, but alone is not sufficient.

▼ History

Kiernan (1996) gave a biographic account of Murray L. Barr (1908-1995), for whom the Barr body was named based on description of the sex chromatin body by Barr and Bertram (1949).

▼ ALLELIC VARIANTS ( 1 Selected Example):

Table View ClinVar

.0001 X INACTIVATION, FAMILIAL SKEWED, 1

XIST, C-G, -43

RCV000010433

Plenge et al. (1997) identified a mutation in the XIST minimal promoter in multiple females in a family reported by Rupert et al. (1995) as showing nonrandom X chromosome inactivation (300087). The mutation was a C-to-G transversion at position -43 in the minimal promoter on the preferentially inactive X chromosome. The -43 mutation created a novel HhaI restriction site that was used to test for the presence of the mutation in a large series of unrelated females, representing 1,166 independent X chromosomes. The mutation was found on only 1 additional chromosome in this dataset, ruling out that the mutation represented a common polymorphism. The heterozygous female identified by this screen was from a large family with Snyder-Robinson mental retardation syndrome (309583), which maps to Xp22.12-p21.3. Haplotype analysis indicated that the 2 families were not related. Subsequent analysis in the second family revealed 6 additional females and 4 males who had inherited the XIST mutation.

▼ See Also:

Cattanach et al. (1970); Cattanach et al. (1969); Daly et al. (1977); Nakagome (1982); Rastan and Cattanach (1983); Tantravahi et al. (1983)

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Contributors:

Bao Lige - updated : 03/05/2024

Ada Hamosh - updated : 01/05/2021
Ada Hamosh - updated : 08/28/2020
Ada Hamosh - updated : 05/13/2019
Ada Hamosh - updated : 09/28/2016
Ada Hamosh - updated : 09/24/2015
Ada Hamosh - updated : 6/26/2015
Ada Hamosh - updated : 1/15/2014
Ada Hamosh - updated : 10/21/2013
Ada Hamosh - updated : 10/2/2013
Ada Hamosh - updated : 8/29/2012
Ada Hamosh - updated : 5/30/2012
Patricia A. Hartz - updated : 4/16/2012
Patricia A. Hartz - updated : 2/13/2012
Ada Hamosh - updated : 7/8/2011
Ada Hamosh - updated : 8/27/2009
Matthew B. Gross - reorganized : 8/10/2009
Patricia A. Hartz - updated : 7/24/2009
Ada Hamosh - updated : 2/18/2009
Ada Hamosh - updated : 7/11/2008
Ada Hamosh - updated : 5/2/2008
George E. Tiller - updated : 4/29/2008
Ada Hamosh - updated : 8/1/2006
Ada Hamosh - updated : 4/19/2006
Cassandra L. Kniffin - updated : 3/28/2006
Ada Hamosh - updated : 12/12/2005
Patricia A. Hartz - updated : 11/10/2005
Ada Hamosh - updated : 3/10/2004
Ada Hamosh - updated : 12/16/2003
Ada Hamosh - updated : 4/15/2003
Patricia A. Hartz - updated : 3/25/2003
Stylianos E. Antonarakis - updated : 11/26/2002
Victor A. McKusick - updated : 9/11/2002
Paul J. Converse - updated : 4/4/2002
George E. Tiller - updated : 2/12/2002
Ada Hamosh - updated : 1/17/2002
Victor A. McKusick - updated : 1/7/2002
Stylianos E. Antonarakis - updated : 1/7/2002
Ada Hamosh - updated : 11/29/2000
Victor A. McKusick - updated : 8/7/2000
Stylianos E. Antonarakis - updated : 6/20/2000
Victor A. McKusick - updated : 2/17/2000
Victor A. McKusick - updated : 1/18/2000
Victor A. McKusick - updated : 11/23/1999
Stylianos E. Antonarakis - updated : 10/25/1999
Ada Hamosh - updated : 4/8/1999
Stylianos E. Antonarakis - updated : 9/30/1998
Victor A. McKusick - updated : 6/25/1998
Stylianos E. Antonarakis - updated : 5/20/1998
Ada Hamosh - updated : 1/16/1998
Victor A. McKusick - updated : 10/28/1997
Victor A. McKusick - updated : 9/19/1997
Victor A. McKusick - updated : 8/20/1997
Victor A. McKusick - updated : 6/9/1997
Victor A. McKusick - updated : 5/15/1997
Victor A. McKusick - updated : 3/3/1997
Victor A. McKusick - updated : 2/11/1997

Creation Date:

Victor A. McKusick : 6/4/1986

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* 314670

X INACTIVATION-SPECIFIC TRANSCRIPT; XIST

Other entities represented in this entry:

X INACTIVATION CENTER, INCLUDED; XIC, INCLUDED

HGNC Approved Gene Symbol: XIST

Cytogenetic location: Xq13.2 Genomic coordinates (GRCh38): X:73,820,651-73,852,753 (from NCBI)

Gene-Phenotype Relationships

Location	Phenotype	Phenotype MIM number	Inheritance	Phenotype mapping key
Xq13.2	X-inactivation, familial skewed	300087		3

TEXT

Description

Cloning and Expression

Gene Structure

Brown et al. (1992) determined that the XIST gene contains at least 8 exons.

Lafreniere et al. (1993) demonstrated that the transcriptional orientation of XIST is cen--3-prime--XIST--5-prime--qter.

Mapping

XIST Gene

Borsani et al. (1991) found that mouse Xist is located in the mouse X inactivation center region. Brockdorff et al. (1991) likewise found that mouse Xist maps to the XIC region.

X Inactivation Center

Gene Function

Reviews

Willard (1996) gave a review of the X inactivation center and the role of XIST in X chromosome inactivation.

Boumil and Lee (2001) reviewed the roles of Xist and Tsix in X inactivation.

Molecular Genetics

Familial Skewed X Inactivation

Cytogenetics

Ring X Chromosomes

Evolution

Animal Model

Nomenclature

XIC, for 'X inactivation center,' refers to a region on the X chromosome. XIST refers to a specific gene within that region that is necessary for X inactivation, but alone is not sufficient.

History

Kiernan (1996) gave a biographic account of Murray L. Barr (1908-1995), for whom the Barr body was named based on description of the sex chromatin body by Barr and Bertram (1949).

ALLELIC VARIANTS 1 Selected Example):

.0001 X INACTIVATION, FAMILIAL SKEWED, 1

XIST, C-G, -43
SNP: rs773396320, gnomAD: rs773396320, ClinVar: RCV000010433

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Contributors:

Bao Lige - updated : 03/05/2024
Ada Hamosh - updated : 01/05/2021
Ada Hamosh - updated : 08/28/2020
Ada Hamosh - updated : 05/13/2019
Ada Hamosh - updated : 09/28/2016
Ada Hamosh - updated : 09/24/2015
Ada Hamosh - updated : 6/26/2015
Ada Hamosh - updated : 1/15/2014
Ada Hamosh - updated : 10/21/2013
Ada Hamosh - updated : 10/2/2013
Ada Hamosh - updated : 8/29/2012
Ada Hamosh - updated : 5/30/2012
Patricia A. Hartz - updated : 4/16/2012
Patricia A. Hartz - updated : 2/13/2012
Ada Hamosh - updated : 7/8/2011
Ada Hamosh - updated : 8/27/2009
Matthew B. Gross - reorganized : 8/10/2009
Patricia A. Hartz - updated : 7/24/2009
Ada Hamosh - updated : 2/18/2009
Ada Hamosh - updated : 7/11/2008
Ada Hamosh - updated : 5/2/2008
George E. Tiller - updated : 4/29/2008
Ada Hamosh - updated : 8/1/2006
Ada Hamosh - updated : 4/19/2006
Cassandra L. Kniffin - updated : 3/28/2006
Ada Hamosh - updated : 12/12/2005
Patricia A. Hartz - updated : 11/10/2005
Ada Hamosh - updated : 3/10/2004
Ada Hamosh - updated : 12/16/2003
Ada Hamosh - updated : 4/15/2003
Patricia A. Hartz - updated : 3/25/2003
Stylianos E. Antonarakis - updated : 11/26/2002
Victor A. McKusick - updated : 9/11/2002
Paul J. Converse - updated : 4/4/2002
George E. Tiller - updated : 2/12/2002
Ada Hamosh - updated : 1/17/2002
Victor A. McKusick - updated : 1/7/2002
Stylianos E. Antonarakis - updated : 1/7/2002
Ada Hamosh - updated : 11/29/2000
Victor A. McKusick - updated : 8/7/2000
Stylianos E. Antonarakis - updated : 6/20/2000
Victor A. McKusick - updated : 2/17/2000
Victor A. McKusick - updated : 1/18/2000
Victor A. McKusick - updated : 11/23/1999
Stylianos E. Antonarakis - updated : 10/25/1999
Ada Hamosh - updated : 4/8/1999
Stylianos E. Antonarakis - updated : 9/30/1998
Victor A. McKusick - updated : 6/25/1998
Stylianos E. Antonarakis - updated : 5/20/1998
Ada Hamosh - updated : 1/16/1998
Victor A. McKusick - updated : 10/28/1997
Victor A. McKusick - updated : 9/19/1997
Victor A. McKusick - updated : 8/20/1997
Victor A. McKusick - updated : 6/9/1997
Victor A. McKusick - updated : 5/15/1997
Victor A. McKusick - updated : 3/3/1997
Victor A. McKusick - updated : 2/11/1997

Creation Date:

Victor A. McKusick : 6/4/1986

Edit History:

mgross : 03/05/2024
alopez : 02/17/2021
mgross : 01/05/2021
alopez : 08/28/2020
alopez : 08/28/2020
carol : 05/14/2019
alopez : 05/13/2019
alopez : 03/05/2019
alopez : 09/28/2016
alopez : 09/24/2015
alopez : 7/30/2015
alopez : 6/26/2015
alopez : 1/15/2014
alopez : 10/21/2013
alopez : 10/2/2013
mgross : 2/4/2013
mgross : 1/11/2013
alopez : 9/4/2012
terry : 8/29/2012
mgross : 6/7/2012
mgross : 6/7/2012
alopez : 6/6/2012
alopez : 6/6/2012
terry : 5/30/2012
terry : 4/16/2012
mgross : 4/10/2012
mgross : 4/10/2012
terry : 2/13/2012
alopez : 8/8/2011
alopez : 7/13/2011
terry : 7/8/2011
carol : 4/7/2011
alopez : 11/10/2010
terry : 12/17/2009
terry : 12/17/2009
alopez : 9/8/2009
terry : 8/27/2009
terry : 8/27/2009
mgross : 8/10/2009
mgross : 8/10/2009
terry : 7/24/2009
alopez : 2/24/2009
terry : 2/18/2009
alopez : 7/14/2008
alopez : 7/14/2008
terry : 7/11/2008
alopez : 5/7/2008
terry : 5/2/2008
wwang : 4/30/2008
terry : 4/29/2008
wwang : 2/7/2007
carol : 11/27/2006
alopez : 8/2/2006
terry : 8/1/2006
alopez : 4/21/2006
terry : 4/19/2006
wwang : 4/6/2006
ckniffin : 3/28/2006
alopez : 12/13/2005
terry : 12/12/2005
mgross : 11/21/2005
terry : 11/10/2005
alopez : 3/11/2004
terry : 3/10/2004
alopez : 2/18/2004
tkritzer : 1/5/2004
alopez : 12/17/2003
terry : 12/16/2003
alopez : 11/3/2003
carol : 9/11/2003
alopez : 4/17/2003
terry : 4/15/2003
mgross : 3/25/2003
mgross : 11/26/2002
mgross : 11/26/2002
carol : 9/19/2002
tkritzer : 9/11/2002
tkritzer : 9/11/2002
mgross : 4/4/2002
cwells : 2/18/2002
cwells : 2/12/2002
alopez : 2/5/2002
alopez : 1/22/2002
terry : 1/17/2002
carol : 1/7/2002
terry : 1/7/2002
mgross : 1/7/2002
cwells : 11/20/2001
cwells : 5/3/2001
mgross : 12/1/2000
terry : 11/29/2000
mcapotos : 8/28/2000
mcapotos : 8/11/2000
terry : 8/7/2000
mgross : 6/20/2000
alopez : 2/29/2000
terry : 2/17/2000
mcapotos : 1/28/2000
mcapotos : 1/27/2000
terry : 1/18/2000
terry : 11/30/1999
carol : 11/24/1999
terry : 11/23/1999
mgross : 10/25/1999
alopez : 4/8/1999
alopez : 4/8/1999
alopez : 3/30/1999
alopez : 3/29/1999
carol : 3/26/1999
terry : 3/17/1999
carol : 9/30/1998
alopez : 6/29/1998
terry : 6/25/1998
carol : 5/20/1998
alopez : 1/16/1998
alopez : 10/28/1997
jenny : 10/28/1997
terry : 10/28/1997
mark : 9/19/1997
terry : 9/19/1997
jenny : 8/22/1997
terry : 8/20/1997
terry : 6/23/1997
alopez : 6/9/1997
jenny : 5/15/1997
terry : 5/12/1997
mark : 5/7/1997
terry : 5/2/1997
mark : 3/27/1997
mark : 3/3/1997
terry : 2/28/1997
terry : 2/11/1997
terry : 2/5/1997
terry : 12/30/1996
terry : 12/11/1996
terry : 11/7/1996
joanna : 7/8/1996
mark : 2/26/1996
terry : 2/19/1996
mark : 2/13/1996
terry : 2/7/1996
terry : 8/30/1994
jason : 7/13/1994
pfoster : 4/4/1994
mimadm : 4/1/1994
carol : 2/9/1994

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X INACTIVATION-SPECIFIC TRANSCRIPT; XIST

TEXT

▼ Description

▼ Cloning and Expression

▼ Gene Structure

▼ Mapping

▼ Gene Function

▼ Molecular Genetics

▼ Cytogenetics

▼ Evolution

▼ Animal Model

▼ Nomenclature

▼ History

▼ ALLELIC VARIANTS ( 1 Selected Example):

.0001 X INACTIVATION, FAMILIAL SKEWED, 1

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* 314670

X INACTIVATION-SPECIFIC TRANSCRIPT; XIST

Gene-Phenotype Relationships

TEXT

Description

Cloning and Expression

Gene Structure

Mapping

Gene Function

Molecular Genetics

Cytogenetics

Evolution

Animal Model

Nomenclature

History

ALLELIC VARIANTS 1 Selected Example):

.0001 X INACTIVATION, FAMILIAL SKEWED, 1

See Also:

REFERENCES

▼

External Links