XIST (gene)
Encyclopedia
Xist is an RNA gene
on the X chromosome
of the placental mammals
that acts as 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.
is an early developmental
process in mammalian females that transcriptionally silences one of the pair of X chromosome
s, 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.
X-inactivation process occurs in mice even in the absence of this gene via epigenetic regulation
, but Xist is required to stabilize this silencing.
structures that are each composed of four repeats. Although the exact function of the A-region is uncertain, it was shown that the entire region is needed for efficient binding to the Suz12 protein.
Turner's Syndrome is one example of where dosage compensation does not equally express the X chromosome, and in females one of the X chromosomes is missing or has abnormalities, which leads to physical abnormalities and also gonadal dysfunction in females due to the one missing or abnormal X chromosome. Turner's syndrome is also referred to as a monosomy X condition.
with BRCA1
.
Non-coding RNA
A non-coding RNA is a functional RNA molecule that is not translated into a protein. Less-frequently used synonyms are non-protein-coding RNA , non-messenger RNA and functional RNA . The term small RNA is often used for short bacterial ncRNAs...
on the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
of the placental mammals
Eutheria
Eutheria is a group of mammals consisting of placental mammals plus all extinct mammals that are more closely related to living placentals than to living marsupials . They are distinguished from noneutherians by various features of the feet, ankles, jaws and teeth...
that acts as 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
Jpx (gene)
In molecular biology, JPX transcript, XIST activator , also known as Jpx, is a long non-coding RNA. In humans, it is located on the X chromosome. It was identified during sequence analysis of the X inactivation centre, surrounding the Xist gene. Jpx upregulates expression of Xist....
and Ftx
Ftx (gene)
In molecular biology, FTX transcript, XIST regulator , also known as FTX , is a long non-coding RNA. In humans, it is located on the X chromosome. It was identified during sequence analysis of the X inactivation centre, surrounding the XIST gene. FTX contains several microRNAs within its introns...
) and two protein genes
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
(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
RNA splicing
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
and polyadenylation
Polyadenylation
Polyadenylation is the addition of a poly tail to an RNA molecule. The poly tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In eukaryotes, polyadenylation is part of the process that produces mature messenger RNA for translation...
. 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
Pseudogene
Pseudogenes are dysfunctional relatives of known genes that have lost their protein-coding ability or are otherwise no longer expressed in the cell...
. 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.
Function
X inactivationX-inactivation
X-inactivation is a process by which one of the two copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by packaging into transcriptionally inactive heterochromatin...
is an early developmental
Developmental biology
Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...
process in mammalian females that transcriptionally silences one of the pair of X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
s, thus providing dosage equivalence between males and females (see dosage compensation
Dosage compensation
Dosage compensation, also known as Ohno's Hypothesis, is a hypothetical genetic regulatory mechanism which operates to equalize the phenotypic expression of characteristics determined by genes on the X chromosome so that they are equally expressed in the human XY male and the XX female. In 2006,...
). The process is regulated by several factors, including a region of chromosome X called the X inactivation center (XIC). The XIST gene is expressed
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
exclusively from the XIC of the inactive X chromosome. The transcript is spliced
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
but apparently does not encode a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
. The transcript remains in the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
where it coats the inactive X chromosome. Alternatively spliced transcript variants have been identified, but their full length sequences have not been determined.
X-inactivation process occurs in mice even in the absence of this gene via epigenetic regulation
Epigenetics
In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence – hence the name epi- -genetics...
, but Xist is required to stabilize this silencing.
Gene location
The human Xist RNA gene is located on the X chromosome of the long (q) arm of chromosome. Xist RNA gene consists of conserved repeats within its structure and is also highly localized in the nucleus. The Xist RNA gene consists of an A region, which contains 8 repeats which are separated by U-rich spacers. The A region appears to contain two long stem-loop structures each that include four repeats. An ortholog of the Xist RNA gene from humans has been also identified in mice. The mouse ortholog is a 15 kb Xist RNA gene that is also localized in the nucleus; however, does not consist of any conserved repeats. The gene also consists of an Xist Inactivation Center (XIC), which plays a major role in X inactivation.A region
The Xist RNA contains a region of conservation called the A region that contains up to nine repeated elements. It has recently been shown that in human and mouse Xist RNAs the A region comprises two long stem-loopStem-loop
Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded DNA or, more commonly, in RNA. The structure is also known as a hairpin or hairpin loop. It occurs when two regions of the same strand, usually complementary in nucleotide sequence when read in opposite directions,...
structures that are each composed of four repeats. Although the exact function of the A-region is uncertain, it was shown that the entire region is needed for efficient binding to the Suz12 protein.
X Inactivation Center (XIC)
The Xist RNA gene consists of an X Inactivation Center (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.Tsix antisense transcript
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 Xist gene expression, which negatively regulating the Xist gene. The mechanism behind how Tsix modulates Xist activity in cis is poorly understood; however, there are a few theories on its mechanism. One theory believes that Tsix is believed to be involved in chromatin modification at the Xist locus and another believes that transcriptional factors of pluripotent cells play a role in Xist repression.Methylation of the Xist promotor by DNA methyl transferases
The Tsix antisense is believed to activate DNA methyl transferases that methylate the Xist promoter, in return resulting in inhibition of the Xist promoter and thus the expression of the Xist gene. Methylation produces an active chromatin structure, which recruits transcriptional factors and thus allows for transcription to occur, therefore in this case the transcription of Xist.dsRNA and RNAi pathway
A dsRNA and RNAi pathway have been also proposed to play a role in regulation of the Xist Promoter. Dicer is an RNAi enzyme and it is believed to cleave the duplex of Xist and Tsix at the beginning of X inactivation, to small ~30 nucleotide RNAs, which have been termed xiRNAs, These xiRNAs are believed to be involved in repressing Xist on the probable active X chromosome based upon studies. A study was conducted where normal endogenous Dicer levels were decreased to 5%, which led to an increase in Xist expression in undifferentiated cells, thus supporting the role of xiRNAs in Xist repression. The role and mechanism of xiRNAs is still under examination and debate.Pluripotent cells transcriptional factors
Pluripotent cells consist of transcriptional factors Nanog, Oct4 and Sox2 that seem to play a role in repressing Xist. In the absence of Tsix in pluripotent cells, Xist is repressed, where a mechanism has been proposed that these transcriptional factors cause splicing to occur at intron 1 at the binding site of these factors on the Xist gene, which inhibits Xist expression A study was conducted where Nanog or Oct4 transcriptional factors were depleted in pluripotent cells, which resulted in the upregulation of Xist. From this study, it is proposed that Nanog and Oct4 are involved in the repression of Xist expression.Polycomb Repressor Complex 2 (PRC2)
PRC2 consist of a class of polycomb group proteins that are involved in catalyzing the trimethylation of histone H3 on lysine 27 (K27), which results in chromatin repression, and thus leads to transcriptional silencing. SUZ12 is component of the PCR2 and it consists of a zinc finger domain. The zinc finger domain is believed to bind to the RNA molecule. 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 dosage compensation mechanisms that allow for equal expression of the X and autosomal chromosomes. Different species have different dosage compensation methods, with all of the methods involving the regulation of an X chromosome from one of the either sexes. Some methods involved in dosage compensation to inactive one of the X chromosomes from one of the sexes are Tsix antisense gene, DNA methylation and DNA acetylation; however, the definite mechanism of X inactivation is still poorly understood. If one of the X chromosomes is not inactivated or is partially expressed, it could lead to over expression of the X chromosome and it could be lethal in some cases.Turner's Syndrome is one example of where dosage compensation does not equally express the X chromosome, and in females one of the X chromosomes is missing or has abnormalities, which leads to physical abnormalities and also gonadal dysfunction in females due to the one missing or abnormal X chromosome. Turner's syndrome is also referred to as a monosomy X condition.
X inactivation cycle
Xist expression and X inactivation change throughout embryonic development. In early embryogenesis, the oocyte and sperm do not express Xist and the X chromosome remains active. After fertilization, when the cells are in the 2 to 4 cell stage, Xist transcripts are expressed from the paternal X chromosome, which in return cause the paternal X chromosome to become imprinted and inactivated. The cells develop into pluripotent cells (the inner cell mass) where the imprint is removed, which leads to the downregulation of Xist and thus reactivation of the inactive X chromosome. The epiblast cells are then formed and they begin to differentiate, and the Xist is upregulated from either of the two X chromosomes and at random, an X is inactivated and the Xist allele is turned off in the active X chromosome. In maturing XX primordial germ cells, Xist is downregulated and X reactivation occurs once again.Interactions
XIST (gene) has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with BRCA1
BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
.