XIST

7503213742n/aENSMUSG00000086503n/an/an/an/an/an/aXist (X-inactive specific transcript) is an RNA gene on the X chromosome of the placental mammals that acts as a major effector of the X inactivation process. It is a component of the Xic – X-chromosome inactivation centre – along with two other RNA genes (Jpx and Ftx) and two protein genes (Tsx and Cnbp2). The Xist RNA, a large (17 kb in humans) transcript, is expressed on the inactive chromosome and not on the active one. It is processed in a similar way to mRNAs, through splicing and polyadenylation. However, it remains untranslated. It has been suggested that this RNA gene evolved at least partly from a protein coding gene that became a pseudogene. The inactive X chromosome is coated with this transcript, which is essential for the inactivation. X chromosomes lacking Xist will not be inactivated, while duplication of the Xist gene on another chromosome causes inactivation of that chromosome. The human XIST gene was discovered by Carolyn J. Brown in the laboratory of Hunt Willard. Xist (X-inactive specific transcript) is an RNA gene on the X chromosome of the placental mammals that acts as a major effector of the X inactivation process. It is a component of the Xic – X-chromosome inactivation centre – along with two other RNA genes (Jpx and Ftx) and two protein genes (Tsx and Cnbp2). The Xist RNA, a large (17 kb in humans) transcript, is expressed on the inactive chromosome and not on the active one. It is processed in a similar way to mRNAs, through splicing and polyadenylation. However, it remains untranslated. It has been suggested that this RNA gene evolved at least partly from a protein coding gene that became a pseudogene. The inactive X chromosome is coated with this transcript, which is essential for the inactivation. X chromosomes lacking Xist will not be inactivated, while duplication of the Xist gene on another chromosome causes inactivation of that chromosome. The human XIST gene was discovered by Carolyn J. Brown in the laboratory of Hunt Willard. X inactivation is an early developmental process in mammalian females that transcriptionally silences one of the pair of X chromosomes, thus providing dosage equivalence between males and females (see dosage compensation). The process is regulated by several factors, including a region of chromosome X called the X inactivation center (XIC). The XIST gene is expressed exclusively from the XIC of the inactive X chromosome. The transcript is spliced but apparently does not encode a protein. The transcript remains in the nucleus where it coats the inactive X chromosome. Alternatively spliced transcript variants have been identified, but their full length sequences have not been determined. 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. X-inactivation process occurs in mice even in the absence of this gene via epigenetic regulation, but Xist is required to stabilize this silencing. The human Xist RNA gene is located on the long (q) arm of the X chromosome. The Xist RNA gene consists of conserved repeats within its structure and is also largely localized in the nucleus. The Xist RNA gene consists of an A region, which contains 8 repeats separated by U-rich spacers. The A region appears to contain two long stem-loop structures that each include four repeats. An ortholog of the Xist RNA gene in humans has been identified in mice. This ortholog is a 15 kb Xist RNA gene that is also localized in the nucleus. However, the ortholog does not consist of conserved repeats. The gene also consists of an Xist Inactivation Center (XIC), which plays a major role in X inactivation. The Xist RNA contains a region of conservation called the repeat A (repA) region that contains up to nine repeated elements. 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. 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. 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. The Xist RNA gene lies within the X-Inactivation Centre (XIC), which plays a major role in Xist expression and X inactivation. 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. X inactivation plays a key role in dosage compensation. The Tsix antisense gene is a transcript of the Xist gene at the XIC center. The Tsix antisense transcript acts in cis to repress the transcription of Xist, which negatively regulates its expression. The mechanism behind how Tsix modulates Xist activity in cis is poorly understood; however, there are a few theories on its mechanism. One theory is that Tsix is involved in chromatin modification at the Xist locus and another is that transcription factors of pluripotent cells play a role in Xist repression.