Disease relevance of XIC

• Although low expression was present in testicular parenchyma with spermatogenesis, XIST was expressed at a higher level in parenchyma with carcinoma in situ, the precursor lesion of seminomas and nonseminomas [1].
• Reactivation of an inactive human X chromosome introduced into mouse embryonal carcinoma cells by microcell fusion with persistent expression of XIST [2].
• In addition, the HDAC8 gene is localized on the X chromosome at position q13, which is close to the XIST gene and chromosomal breakpoints associated with preleukemia [3].
• Association between favorable neuroblastoma and high expression of the novel metalloproteinase gene, nbla3145/XCE, cloned by differential screening of the full-length-enriched oligo-capping neuroblastoma cDNA libraries [4].
• Our data suggest that XIST expression may be a potential marker for chemotherapeutic responses in ovarian cancer [5].

Psychiatry related information on XIC

• The abnormal phenotype and/or mental retardation seen in persons with small marker X (mar(X)) chromosomes has been hypothesized to be due to the loss of the X inactivation center (XIC) at Xq13.2, resulting in two active copies of genes in the pericentromeric region [6].

High impact information on XIC

• Tsix, a gene antisense to Xist at the X-inactivation centre [7].
• Mammalian X-chromosome inactivation is thought to be controlled by the X inactivation centre (XIC, X-controlling element -Xce-in mice) [8].
• Expression of the X-inactivation-associated gene XIST during spermatogenesis [8].
• We now report the presence of Xist/XIST transcripts in newborn and adult mouse testes, and in human testicular tissue with normal spermatogenesis, but not in the testes of patients who lack germ cells [8].
• The Xist sequence contains a number of regions comprised of tandem repeats [9].

Biological context of XIC

• One feature of virtually all models of X inactivation is the existence of an X-inactivation centre (XIC) required in cis for inactivation to occur [10].
• Human TSIX produces a >30-kb transcript that is expressed only in cells of fetal origin; it is expressed from human XIC transgenes in mouse embryonic stem cells and from human embryoid-body-derived cells, but not from human adult somatic cells [11].
• This cluster also includes the breakpoint of a translocated X;14 chromosome used to define the proximal border of the XIC region [12].
• Here we present a refined mapping of the XIC-containing region using the breakpoint of a late replicating rearranged X (rea(X)), and the initial characterization of a set of 40 yeast artificial chromosomes (YACs) derived from the XIC-containing region [13].
• We have identified at least 9 CpG-rich islands within this region, and have discovered a large (approximately 125 kb) inverted duplication proximal to the XIC based on symmetrical restriction patterns and homologous probes [13].

Anatomical context of XIC

• We have used human/mouse hybrid cell lines to derive a pulsed-field map of the Xq13 region of the human X chromosome, in the vicinity of the X inactivation center (XIC) [12].
• An overall chromatin difference in the chromosomes may influence imprinted paternal Xist expression in early embryos and in the trophectoderm and primary endoderm populations that segregate early from the totipotent progenitors [14].
• In addition, transcripts of XIST were detected in both male (hence from the maternally inherited allele) and female preimplantation embryos [15].
• XIST expression in human oocytes and preimplantation embryos [15].
• 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 [15].

Associations of XIC with chemical compounds

• Other anomalous cases include 5aC-induced advances in replication time for genes such as XIST and F9 whose transcription was unaltered by treatment [16].
• Expression patterns of parental alleles in F1 hybrids indicated preferential paternal expression at the XIST locus solely in the chorion of females, whereas analysis of the IGF2 and GTL2 loci indicated preferential paternal and maternal expression of alleles, respectively, in both fetal and placental tissues [17].

Regulatory relationships of XIC

• Now, using RNA FISH for cellular localization of transcripts in human fetal cells, we show that human TSIX antisense transcripts are unable to repress XIST [18].

Other interactions of XIC

• Localisation of BRX, its human homolog has shown the gene to be located within the orthologous but inverted human CDX4-XIST segment [19].
• Based on replication studies, a two-fold higher than normal phosphoglycerate kinase activity and absence of XIST expression, we conclude that the duplicated region is not subject to X-inactivation, despite the presence of two XICs [20].
• Small marker chromosomes (SMC) associated with severe Turner syndrome (TS) variants often represent reduced X chromosomes lacking the X inactivation center (XIC), perturbed dosage compensation, and unbalanced gene expression [21].

Analytical, diagnostic and therapeutic context of XIC

• In addition, the XIST transcript has been localized within the nucleus to the Barr body by RNA in situ hybridization [22].
• Furthermore, PCR amplification of human cDNA libraries and RNA fluorescence in situ hybridization (RNA-FISH) demonstrate that the human XIST gene has additional 2.8 kb downstream sequences which have not been documented as a part of the gene [23].
• By RT-PCR analysis and the androgen receptor assay, it was shown that in one of these mentally retarded patients, the XIST on the mar(X) was not transcribed and consequently the mar(X) was not inactivated, leading to functional disomy X [24].
• Comparative sequence analysis of the XIST locus and adjacent regions suggests that repression of the maternal allele in the bovine is controlled by a different mechanism than in mice, further reinforcing the importance of comparative analysis of imprinting [17].
• The fetus we describe is the first male with a mosaic XIST-negative r(X) chromosome identified at prenatal diagnosis [25].

References