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X-Inactivation - Wikipedia, The Free Encyclopedia

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X-inactivation - Wikipedia, the free encyclopedia X-inactivation From Wikipedia, the free encyclopedia X-inactivation (also called lyonization) 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 it being packaged in such a way that it has a transcriptionally inactive structure called heterochromatin. As female mammals have two X chromosomes, X-inactivatio
  The coloration of tortoiseshell andcalico cats is a visible manifestationof X-inactivation. The black andorange alleles of a fur coloration genereside on the X chromosome. For anygiven patch of fur, the inactivation of an X chromosome that carries onegene results in the fur color of theother, active gene. X-inactivation From Wikipedia, the free encyclopedia X-inactivation (also called lyonization ) is a process by which one of the two copies of the X chromosome present in female mammals isinactivated. The inactive X chromosome is silenced by it being packagedin such a way that it has a transcriptionally inactive structure calledheterochromatin. As female mammals have two X chromosomes,X-inactivation prevents them from having twice as many X chromosomegene products as males, which only possess a single copy of the Xchromosome (see dosage compensation). The choice of which Xchromosome will be inactivated is random in placental mammals such ashumans, but once an X chromosome is inactivated it will remain inactivethroughout the lifetime of the cell and its descendants in the organism.Unlike the random X-inactivation in placental mammals, inactivation inmarsupials applies exclusively to the paternally derived X chromosome. Contents 1 History2 Mechanism2.1 Timing2.2 Selection of one active X chromosome2.3 Chromosomal component2.4 Xist and Tsix RNAs2.5 Silencing2.6 Barr bodies2.6.1 Expressed genes on the inactive X chromosome3 Uses in experimental biology4 See also5 References6 Further reading History In 1959 Susumu Ohno showed that the two X-chromosomes of mammals were different: one appeared like theautosomes; the other was condensed and heterochromatic. [3] This finding suggested, independently to twogroups of investigators, that one of the X-chromosomes underwent inactivation. In 1961, Mary Lyon proposedthe random inactivation of one female X chromosome to explain the mottled phenotype of female miceheterozygous for coat color genes. [4] The Lyon hypothesis also accounted for the findings that one copy of theX chromosome in female cells was highly condensed, and that mice with only one copy of the X chromosomedeveloped as infertile females. This suggested [5] to Ernest Beutler, studying heterozygous females for Glucose-6-phosphate dehydrogenase (G6PD) deficiency, that there were two red cell populations of erythrocytes in suchheterozygotes: deficient cells and normal cells, [6] depending on whether the inactivated X chromosome contains X-inactivation - Wikipedia, the free encyclopedia of 89/22/2013 1:08 PM   Nucleus of a female cell. Top: BothX-chromosomes are detected, byFISH. Bottom: The same nucleusstained with a DNA stain (DAPI).The Barr body is indicated by thearrow, it identifies the inactive X(Xi).An interphase female humanfibroblast cell. [1] Arrows point to sexchromatin on DNA (DAPI) in cellnucleus(left), and to thecorresponding X chromatin (right).Left: DNA (DAPI)-stained nucleus.Arrow indicates the location of Barr  body(Xi). Right: DNA associatedhistones protein detected the normal or defective G6PD allele.The Lyon hypothesis became the Lyon Law on July 22, 2011 at theEMBO 50-years of X-inactivation conference in Oxford. [7] Mechanism Timing All mouse cells undergo an early, imprinted inactivation of the paternally-derived X chromosome in two-cell or four-cell stageembryos. [8][9][10] The extraembryonic tissues (which give rise to the placenta and other tissues supporting the embryo) retain this earlyimprinted inactivation, and thus only the maternal X chromosome isactive in these tissues.In the early blastocyst, this initial, imprinted X-inactivation is reversedin the cells of the inner cell mass (which give rise to the embryo), and inthese cells both X chromosomes become active again. Each of thesecells then independently and randomly inactivates one copy of the Xchromosome. [10] This inactivation event is irreversible during thelifetime of the cell, so all the descendants of a cell which inactivated a particular X chromosome will also inactivate that same chromosome.This phenomenon, which can be observed in the coloration of tortoiseshell cats when females are heterozygous for the X-linked gene,should not be confused with mosaicism, which is a term that specificallyrefers to differences in the genotype of various cell populations in thesame individual; X-inactivation, which is an epigenetic change thatresults in a different phenotype, is not  a change at the genotypic level.For an individual cell or lineage the inactivation is therefore skewed or 'non-random', and this can give rise to mild symptoms in female'carriers' of X-linked genetic disorders. [11] X-inactivation is reversed in the female germline, so that all oocytescontain an active X chromosome. Selection of one active X chromosome  Normal females possess two X chromosomes, and in any given cell onechromosome will be active (designated as Xa) and one will be inactive(Xi). However, studies of individuals with extra copies of the Xchromosome show that in cells with more than two X chromosomes there is still only one Xa, and all theremaining X chromosomes are inactivated. This indicates that the default state of the X chromosome in femalesis inactivation, but one X chromosome is always selected to remain active.It is hypothesized that there is an autosomally-encoded 'blocking factor' which binds to the X chromosome and prevents its inactivation. The model postulates that there is a limiting blocking factor, so once the available blocking factor molecule binds to one X chromosome the remaining X chromosome(s) are not protected frominactivation. This model is supported by the existence of a single Xa in cells with many X chromosomes and by X-inactivation - Wikipedia, the free encyclopedia of 89/22/2013 1:08 PM  The figure shows confocalmicroscopy images from a combinedRNA-DNA FISH experiment for Xistin fibroblast cells from adult femalemouse, demonstrating that Xist RNAis coating only one of theX-chromosomes. RNA FISH signalsfrom Xist RNA are shown in redcolor, marking the inactiveX-chromosome (Xi). DNA FISHsignals from Xist loci are shown inyellow color, marking both active andinactive X-chromosomes (Xa, Xi).The nucleus (DAPI-stained) is shownin blue color. The figure is adaptedfrom:. [2] the existence of two active X chromosomes in cell lines with twice thenormal number of autosomes. [12] Sequences at the X inactivation center ( XIC ), present on the Xchromosome, control the silencing of the X chromosome. Thehypothetical blocking factor is predicted to bind to sequences within theXIC. Chromosomal component The X-inactivation center (or simply XIC) on the X chromosome isnecessary and sufficient to cause X-inactivation. Chromosomaltranslocations which place the XIC on an autosome lead to inactivationof the autosome, and X chromosomes lacking the XIC are notinactivated.The XIC contains four non-translated RNA genes, Xist, Tsix, Jpx andFtx, which are involved in X-inactivation. The XIC also contains binding sites for both known and unknown regulatory proteins. Xist and Tsix RNAs  Main article: Xist  The X-inactive specific transcript (Xist) gene encodes a largenon-coding RNA that is responsible for mediating the specific silencingof the X chromosome from which it is transcribed. [13] The inactive Xchromosome is coated by Xist RNA, [14] whereas the Xa is not (SeeFigure to the right). The Xist gene is the only gene which is expressed from the Xi but not from the Xa. Xchromosomes which lack the Xist gene cannot be inactivated. [15] Artificially placing and expressing the Xistgene on another chromosome leads to silencing of that chromosome. [16][17] Prior to inactivation, both X chromosomes weakly express Xist RNA from the Xist gene. During theinactivation process, the future Xa ceases to express Xist, whereas the future Xi dramatically increases XistRNA production. On the future Xi, the Xist RNA progressively coats the chromosome, spreading out from theXIC; [16] the Xist RNA does not localize to the Xa. The silencing of genes along the Xi occurs soon after coating by Xist RNA.Like Xist, the Tsix gene encodes a large RNA which is not believed to encode a protein. The Tsix RNA istranscribed antisense to Xist, meaning that the Tsix gene overlaps the Xist gene and is transcribed on theopposite strand of DNA from the Xist gene. [18] Tsix is a negative regulator of Xist; X chromosomes lackingTsix expression (and thus having high levels of Xist transcription) are inactivated much more frequently thannormal chromosomes.Like Xist, prior to inactivation, both X chromosomes weakly express Tsix RNA from the Tsix gene. Upon theonset of X-inactivation, the future Xi ceases to express Tsix RNA (and increases Xist expression), whereas Xacontinues to express Tsix for several days. Silencing X-inactivation - Wikipedia, the free encyclopedia of 89/22/2013 1:08 PM  The inactive X chromosome does not express the majority of its genes, unlike the active X chromosome. This isdue to the silencing of the Xi by repressive heterochromatin, which compacts the Xi DNA and prevents theexpression of most genes.Compared to the Xa, the Xi has high levels of DNA methylation, low levels of histone acetylation, low levels of histone H3 lysine-4 methylation, and high levels of histone H3 lysine-9 methylation, all of which are associatedwith gene silencing. [19] Additionally, a histone variant called macroH2A (H2AFY) is exclusively found onnucleosomes along the Xi. [20][21] Barr bodies  Main article: Barr body DNA packaged in heterochromatin, such as the Xi, is more condensed than DNA packaged in euchromatin,such as the Xa. The inactive X forms a discrete body within the nucleus called a Barr body. [22] The Barr body isgenerally located on the periphery of the nucleus, is late replicating within the cell cycle, and, as it contains theXi, contains heterochromatin modifications and the Xist RNA. Expressed genes on the inactive X chromosome A fraction of the genes along the X chromosome escape inactivation on the Xi. The Xist gene is expressed athigh levels on the Xi and is not expressed on the Xa. [23] Many other genes escape inactivation; some areexpressed equally from the Xa and Xi, and others, while expressed from both chromosomes, are still predominantly expressed from the Xa. [24]   [25]   [26] Up to one quarter of genes on the human Xi are capable of escape. [27] Studies in the mouse suggest that in any given cell type, 3 to 15% of genes escape inactivation, andthat escaping gene identity varies between tissues. [28][29] Many of the genes which escape inactivation are present along regions of the X chromosome which, unlike themajority of the X chromosome, contain genes also present on the Y chromosome. These regions are termed pseudoautosomal regions, as individuals of either sex will receive two copies of every gene in these regions(like an autosome), unlike the majority of genes along the sex chromosomes. Since individuals of either sex willreceive two copies of every gene in a pseudoautosomal region, no dosage compensation is needed for females,so it is postulated that these regions of DNA have evolved mechanisms to escape X-inactivation. The genes of  pseudoautosomal regions of the Xi do not have the typical modifications of the Xi and have little Xist RNA bound.The existence of genes along the inactive X which are not silenced explains the defects in humans withabnormal numbers of the X chromosome, such as Turner syndrome (X0) or Klinefelter syndrome (XXY).Theoretically, X-inactivation should eliminate the differences in gene dosage between affected individuals andindividuals with a normal chromosome complement, but in affected individuals the dosage of thesenon-silenced genes will differ as they escape X-inactivation.The precise mechanisms that control escape from X-inactivation are not known, but silenced and escape regionshave been shown to have distinct chromatin marks. [30]   [31] It has been suggested that escape fromX-inactivation might be mediated by expression of long non-coding RNA (lncRNA) within the escapingchromosomal domains. [2] Uses in experimental biology X-inactivation - Wikipedia, the free encyclopedia of 89/22/2013 1:08 PM
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