XChromoInac

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X-Chromosome Inactivation

Stanley M Gartler, University of Washington, Seattle, Washington, USA

Michael A Goldman, San Francisco State University, San Francisco, California, USA

In female mammals, one of the X-chromosomes is transcriptionally silenced byheterochromatin formation to bring about equal expression of X-linked genes in XX

females and XY males.

Introduction

In mammals, the female has two large, gene-rich Xchromosomes, whereas the male has a single X chromo-some and a Y chromosome, which harbours few genes. Ifthe X-linked genes were expressed equally in both sexes,females would produce approximately twice the level of X-linked gene products as would males. Since the greatmajority of genes on the X are not concerned with sexdetermination and reproduction, this difference woulddisturb metabolic balance in one sex or the other. Inmammals and some other groups with XY sex determina-tion, a system has evolved to bring about the equivalence inexpression of X-linked genes in females and males. H. J.Muller, in 1931, dubbed this phenomenon dosage com-pensation (Muller, 1932). Different groups of organismshave evolved distinct strategies to achieve dosage compen-sation. In Drosophila, the transcription rate of the single Xin males is higher than that of the two Xs in females. InCaenorhabditis elegans, the transcription rate is halved inthe females two Xs. In mammals, most of the genes on oneof the Xs in the female are transcriptionally silenced in aprocess called X-chromosome inactivation (XCI), thefocus of this entry.

Muller described dosage compensation in Drosophila. Itwas not until 30 years after that the phenomenon wasclearly recognized in mammals. Based on observations byseveral workers, Mary Lyon, in 1961, proposed that eachcell of a mammal maintained one and only one active Xchromosome, inactivating the other to produce a darkly-staining mass called the sex chromatin or Barr body (Lyon,1961). Morphological evidence for X-chromosome inacti-vation could be seen in the coat colours of variousmammals, including the calico cat a female cat in whichone X chromosome encodes one coat colour, the other adifferent one, and the cats fur is a mosaic of patches havingone coat colour or the other. This early model was, ofcourse, incomplete, but the basic idea of a single active Xchromosome in female cells has stood the test of time.

X Inactivation in Somatic CellsIn the mouse, the two X chromosomes in the early femalembryo are not differentiated, either cytologically ofunctionally; both X chromosomes are active. In the latmorula or early blastocyst stages, the earliest evidence oXCI are seen: asynchrony of deoxyribonucleic acid (DNAreplication between the two Xs, differential gene expression and sex chromatin formation. These differences arfirst observed in the extraembryonic cell lineages that formthe membranes surrounding the embryo. In these cells thpaternal X is preferentially inactivated. At about thtime of gastrulation, random X inactivation occurs i

the epiblast, which contains the cells that will give rise tthe embryo itself. When inactivation occurs in thescells, the paternal or maternal X is randomly chosen tbe inactivated. However, once inactivation has occurredall of the descendants of a cell will have the same X silenThis results in patches of cells having an inactive maternaX, and in patches having an inactive paternal X, explaininthe mosaic pattern of allelic expression seen, for examplein the calico cat.

X Inactivation in the Germline

In contrast to somatic cells, in which X inactivation iextremely stable, inactivation in the germline is cyclic. Ithe female, one X is inactive during the oogonial or mitotphase, while both X chromosomes are active in oogenesiHaving both Xs active may be necessary to permit pairinand recombination in meiosis, which may not be possibleone X is heterochromatic and highly condensed anthe other is not. In the male, with a single X, inactivatiodoes not occur in somatic cells; however, early i

Article Contents

Secondary article

. Introduction

. X Inactivation in Somatic Cells

. X Inactivation in the Germline

. Random and NonrandomX Inactivation

. Stability of X Inactivation

. Genes that Escape Inactivation

. XIST and the X-Inactivation Centre

. DNA Methylation

. Replication Timing

. Histone Acetylation

. Inactive-X-Specific Proteins

. A Model for X-Chromosome Inactivation

. Perspective

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net


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spermatogenesis, the single X is condensed and inacti-vated, possibly to restrict pairing and recombinationbetween the nonhomologous parts of the X and Ychromosomes.

Random and Nonrandom X InactivationX inactivation in somatic cells is generally random, withthe maternal and paternal Xs having an equal probabilityof inactivation.Thus, in females heterozygous for X-linkedtraits, such as haemophilia, about half the cells of the livershould, on average, produce normal clotting factor. This istypically enough to ensure normal blood clotting. If thetrait affects fur colour, as in the calico cat, about half thepatches in the cat should exhibit one phenotype. Statisti-cally, sometimes one X will be inactivated more frequentlythan the other, just as a series of coin tosses may sometimesyield something other than a 50:50 ratio of heads to tails.

Thus, chance could lead to a female heterozygous forhaemophilia in which littleor no clotting factor is producedand the typical symptoms of this disease are observed. Suchstatistical extremes are uncommon.

Aside from statistical fluctuation, preferential inactiva-tion may occur, as in extraembryonic cells or in marsupials,where nonrandom inactivation of the paternal X is the rule(Graves, 1996). Genetic differences on the chromosomemay render one X more likely to undergo inactivation. Inaddition, if one X has a mutant allele whose expressionrenders a cell inviable or inhibits its growth, cellsinactivating the mutant allele will have a selectiveadvantage over cells in which the normal allele is

inactivated. Thus, although inactivation may occurrandomly at first, cells that inactivate the wrong allele willbe overgrown, and the outcome will be an organism inwhich all, or nearly all, cells have the same X inactivated.

Stability of X Inactivation

In placental mammals, the inactive state of the X isgenerally highly stable. As we discuss below, a number offactors collaborate to repress alleles on theinactive X. If allfactors ensuring X inactivation operated independentlyand were functional throughout life, reactivation would

probably not be possible. In the germline, for instance, theinactivation state is cyclic and DNA methylation, animportant repressive factor in somatic cells (see below), isabsent. DNA methylation also seems to be absent from theinactivation system in marsupials, where, even in somaticcells, the inactivationof the X is relatively unstable. Even inmouse somatic cells, some genes on the inactive X arereactivated at low, but significant levels as the animals age.We think that DNA methylation stabilizes the inactivestate. Consistent with this notion, genes that exhibit age-

related reactivation typically do not utilize DNA methylation, while those genes that clearly utilize DNA methylation as a regulatory mechanism are not reactivated witage.

In transformed cell lines, reactivation of some inactivX-linked genes can be induced with 5-azacytidine (5AC),drug known to reverse DNA methylation. The same dru

treatment does not reactivate X-linked genes in normasomatic cells. The reactivation of the X in transformed celprobably occurs because some of the redundant mechanisms maintaining the inactive state are not functioning ithese cells,leaving methylation as one of the only repressivinfluences on X-linked gene expression (Hansen et al1998).

Embryonal carcinoma (EC) cells are derived fromgonadal tumours or embryonic tissues, and maintain theiXs in an active state as long as they remain undifferentiated. However, upon chemical-induced differentiationthe cells will go through X inactivation and one of the twX chromosomes will be silenced (Rastan and Robertson

1985). When female mouse lymphocytes, having one activand one silent X, are fused with EC cells, the inactive Xreactivates. This suggests that there are specific factorpresent in the EC cells that maintain or permit the activstate of both X chromosomes.

Genes that Escape Inactivation

Once, every gene on the inactive X chromosome wabelieved to be transcriptionally silenced. We now knowthat a fair number of genes on human and mouse inactiv

Xs are not repressed (Disteche, 1995).One group of genes escaping X inactivation is found i

the pseudoautosomal region (PAR) at the tip of the shorarm of the human X, a region of homology between the Xand Y chromosomes. Fertility in mammalian malerequires pairing and recombination between the X and Ychromosomes within the PAR. Genes in the PAR arpresent on both the X and Y chromosomes, so no gendosage difference between males and females existcompensation is therefore not necessary and genes in thPAR escape X inactivation.

In addition to the PAR at the tip of the X short arm, second, smaller, PAR is present at the tip of the long arm i

humans. Several genes have been detected there, althoughsurprisingly, one of these is inactivated. Several genes ihumans and mice outside the PAR have functional Ylinked alleles and, as expected, their X-linked counterpartescape inactivation. In these latter cases the X- and Ylinked alleles may differ from one another, as nrecombination between them occurs. Some X-linked genethat escape inactivation have nonfunctional Y-linkecopies (pseudogenes), presumably due to accumulateinactivating mutations. Lastly, there are several reports o


2 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net


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X-linked genes in humans that have no Y-chromosomecounterparts, but still escape inactivation.

Whether in the PAR or not, most genes that escapeinactivation are organized in clusters or functionaldomains in which all of the genes escape inactivation.Such regulatory domains may contain sequence informa-tion specifying the spread or inhibition of an inactivation

signal. Some that escape inactivation may have beenrepressed when X inactivation first occurs, but arereactivated later. Thus the entire X chromosome may beinactivated initially, but selected inactive domains may beinherently unstable and rapidly reversed.

The mouse X appears to be more completely inactivatedthan is the human X, perhaps reflecting the occurrence of alonger evolutionary time for X inactivation in the mouse.Escape from inactivation of the SHOX gene in the humanshort arm PAR is apparently responsible for the shortstature characteristic of Turner syndrome (XO) females. Inmice, where XO is not associated with the phenotypicproblems typical of Turner syndrome in humans, the

SHOX homologue is not X linked.

XIST and the X-Inactivation Centre

A central feature of mammalian X inactivation is itschromosomal nature. With one exception (XIST, de-scribed below), allthe inactivated genes are on one X, whilethe homologue contains the active alleles. This pattern ismost easily explained by a single initiation site from whichinactivation spreads along the restof the chromosome. Theevidence for the existence andlocation of an X-inactivation

centre came from studies of X-autosomal translocationsand deletions which interfered with the manifestation of Xinactivation. Analysis of such translocations allows one toidentify a short segment of the X, termed the X-inactivation centre or XIC, essential for X inactivation.Moreover, in mice, some Xs are more prone to inactivationthan are others. The difference between them resides in alocus called Xce (or X-controlling element), which maps toabout the same position as the XIC identified intranslocation experiments.

A single gene that maps to the XIC and that hasproperties suggesting that it might be the locus essential forthe initiation of X inactivation has been designated X-

inactive specific transcript or XIST. (Human genes aredesignated entirely in capital letters, such as XIST, whereasmouse genes are designated in capitals and lower-caseletters, as in Xist. For convenience here we use a singleacronym, XIST.) XIST is expressed only from the inactiveX (Brown et al., 1991). The ribonucleic acid (RNA)transcript has no significant open reading frame and theproduct remains in the nucleus, coating the inactive X. Thissuggests that XIST is among those loci that produce afunctional RNA molecule that is never translated into a

protein. XIST expression is detected early in preimplantation development, often from both Xs, but well before ansign of X inactivation. However, this early expression iprobably not functional, as the transcript is not stable, iunprocessed, and does not coat the X. In the mouse, thpaternal X begins to accumulate transcripts in the earlmorula, apparently as a result of an imprint in the gamete

that leads to the paternal nonrandom inactivation found iextraembryonic cells. Later, in the inner cell mass, unstabXIST is transcribed from both Xs, but the XIST transcripfrom one or the other X becomes stabilized anaccumulates on that X. Random X inactivation followand XIST transcription from the active X is silencedRecent evidence suggests that alernative promoter utilization or an antisense transcript may be involved in XISTregulation.

Although the properties and map location of XISstrongly suggest that it should be a key element in the Xinactivation process, further experimental evidence warequired to show that this locus is necessary for inactiva

tion of the X chromosome. Thiswas shownthrough the usof various deletions of the promoter or exon region of thXIST gene that prevent production of full-sized XISRNA. In these cases the chromosome bearing the deletiois not inactivated, showing that the XIST gene is requirein cis for inactivation to take place. Further support for critical role of XIST comes from experiments in which thXIST gene and varying amounts of surrounding sequenchave been incorporated into an autosome in malembryonic stem cells. In some cases, where multiple copieof the XIST transgene have been tandemly incorporatedXIST RNA coats the autosome and represses transcription. Although other factors will probably be involved

these experiments indicate that XIST RNA appears tpropagate inactivation by binding to the chromosomfrom which it is expressed. They also imply that specific Xlinked sequences are not required for XIST RNA to coat chromosome.

DNA Methylation

Methylation of the base cytosine occurs enzymaticallafter DNA synthesis and in mammals is restricted to thdinucleotide 5-CpG-3 (CpG). About 7% of CpGs ar

present in clusters called CpG islands, which are usualllocated at the 5 ends of genes and have a relatively higdensity of CpGs. The remaining CpGs are dispersethroughout the genome, usually as singlets. Most CpGislands are unmethylated, but those near inactivated geneon the X chromosome, and those near some imprintegenes on autosomes, are methylated. Methylated CpGislands repress transcription, and the great majority othem in the genome are found on the inactive X in normacells. They are important in maintaining the repressed stat




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of inactive X-linked genes and may also play a role inestablishing X inactivation, as indicated by the fact thatdifferential CpG island methylation occurs close to thetime of inactivation of two X-linked genes that have beenstudied in detail.

Interestingly, most of the dispersed CpGs throughoutthe genome tend to be methylated. There is limited

evidence that the dispersed CpGs on the inactive X maybe hypomethylated relative to the active X, suggesting asimilarity in overall methylation levels on the active andinactive Xs. No evidence exists that the dispersed CpGs,methylated or unmethylated, play a role in gene silencing.

A crucial role of methylation may be in the control ofXIST expression, and therefore the initiation of Xinactivation itself. Methylation analysis of a small clusterof CpGs in the XIST promoter shows that the silent alleleon the active X becomes methylated while the expressedallele on the inactive X is hypomethylated. Developmentalstudies show that the sperm and oocyte are differentiallymethylated in part of the promoter region (sperm

hypermethylated, oocyte hypomethylated) but these dif-ferences in methylation do not persist into preimplantationdevelopment (McDonald et al., 1998). Methylation maynot be the factor responsible for turning XIST on or off inthe first place, but it may function as an imprint andprobably is crucial for keeping the silent copy of XISTstably repressed.

Replication Timing

The inactive X chromosome begins and ends DNA

replication later than its active homologue. Replicationtiming studies of inactivated genes indicate that theyreplicate in the last half of S phase. The appearance of alate-replicating X is observed in early embryogenesis. Infemale embryonic stem cells, which can undergo Xinactivation in culture, a late-replicating X is detectable 2days after the onset of differentiation, well before thesilencing of X-linked genes. Replication timing does notsimply reflect whether a chromosome is active or inactive.For example, the blood clotting factor IX gene on theactive X in nonexpressing cells replicates somewhat earlierthan its allele on the inactive X and replicates even earlier inexpressing cells. Thus,the time of replication appears to be

related to the potential for transcription, whether deter-mined by the chromosome activation state or the cellsdifferentiation phase. Studies with the demethylating agent5AC suggest that methylation at controlling regions mayplay a role in altering timing of replication over domains ofa megabase or more. Although it is possible that latereplication may be merely an effect of the complicatedinactivation process, its early appearance suggests a moresignificant role. There is evidence that late-replicatingdomains are compartmentalized and it is possible that late

replication of the inactive X may play a role in thincorporation of the inactive X into a subnucleacompartment inhibiting transcription.

Histone Acetylation

Acetylation of histones occurs in all plant and animaforms. It occurs at specific lysine residues and is catalyseby histone acetyltransferases (HATs) and deacetylase(HDACs). An association between histone acetylation angene expression has been considered for decades, and haattracted considerable attention recently with the discovery that HATs and HDACs are often identical to, oassociated with, known regulators of transcription. Igeneral, hyperacetylation is associated with gene expression, and hypoacetylation is associated with genesilencingUsing fluorescent antisera for individual acetylated lysinresidues, cytological studies showed that the inactive X

with the exception of regions containing genes that escapinactivation, has a low level of the acetylated isoforms ohistones H2A, H3 and H4 in humans, mice and marsupia(Keohane etal., 1998). That histone deacetylation is not ainitiating event in X inactivation was shown by a study othe development of H4 deacetylation in female embryonistem cells undergoing X inactivation. Increase in XISexpression, late replication onset and initial gene silencinoccur some 2 days before H4 deacetylation of an Xchromosome. Deacetylation of histones on the inactive Xmay be a consequence of other events associated with Xinactivation.

It seems possible that other histone modifications ma

also be associated with the activity state of the inactive XFor example, recently it has been shown that phosphorylation of histone H3 is associated with chromosomcondensation in Tetrahymena.

Inactive-X-Specific Proteins

Although transcriptional proteins bind to the promoteregions of transcribed genes on the active X, all in vivfootprinting attempts to detect transcription inhibitinfactors bound to promoter regions on the inactive X havfailed. Recently, an in vitro binding assay identified

nuclear protein that recognizes the methylated region othe mouse XIST promoter on theactive X. Although mucwork remains to be done, these results suggest thasilencing proteins involved in repressing genes on thinactive X are more likely to function at a chromosomalevel rather than at the level of individual genes. ProbablXIST RNA, which coats the inactive X, does so binteracting with a DNA-binding protein, as suggested byrecent in vitro study showing significant interactionbetween heteronuclear proteins and XIST.




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The most exciting result in this area is the recent findingof a new family of histones, called macroH2A. One of theseis macro histone 2A1(mH2A1) whose N-terminal third ofthe molecule is similar to H2A1, but the remainder ofwhich is unrelated to any known histone (Costanzi andPehrson, 1998). The unique part of mH2A1 was found topreferentially localize with the inactive X-chromosome

during metaphase and interphase in a number of mam-mals, including humans. Surprisingly, other studiesindicate that the nonhistone part of the protein is widelyconserved, and that the gene may have originated beforethe appearance of eukaryotes. Although mH2A1 isenriched on the inactive X, it is found throughout thegenome, in both males and females. It is conceivable thatmH2A1 may interact with XIST RNA in the process of Xinactivation.

A Model for X-Chromosome

InactivationThe study of X-chromosome inactivation is at a juncture inwhich models, grounded in recent data, can be used todirect future research. We can conveniently divide the X-inactivationprocessinto three phases: initiation, spreadingand maintenance.

One of the key features of the initiation of XCI is thechoice of which X is to remain active. In murineextraembryonic cells, where the paternal X is preferentiallyinactivated, choice may follow from the methylationimprint in the sperm XIST gene, the comparable oocyteregion being unmethylated.

In the epiblast where random X inactivation occurs, theearlier methylation imprint of the XIST gene hasdisappeared and both Xs are transcribing unstable XISTRNA. The popular idea has been that choice shouldinvolve selecting an X to remain active rather than theX orXs to become inactive. This reasoning follows from thepresumed difficulty of choice in cells with more than twoXs, where it should be simpler to choose one to be activerather than choosing two or more to become inactive. Oneproposal assumes a limiting amount of an autosomallyproduced blocking factor for which the XICs compete toremain active. A recent study has identified the 3 endoftheXIST gene as a candidate region for the binding site of the

blocking factor (Clerc and Avner, 1998). The requirementfor stabilization of the XIST transcript has led to theproposal of XIST interacting factors affecting stability. Afurther complexity is the fact that mutations in differentparts of the XIST gene can alter susceptibility toinactivation in different ways. It should not be surprisingthat there might be two or more mechanisms for ensuringthat only one X remains active, as the presence of twoactive Xs is apparently lethal (Carrel and Willard, 1998;Panning and Jaenisch, 1998).

XIST is certainly one of the keys to the initiation of Xinactivation. How does it come to act only in cis, neveaffecting the other X-chromosome or the autosomes? Onpossibility is that the inactive X is compartmentalizewithin the nucleus. The inactive X appears isolated in a cecompartment in the form of sex chromatin, generalloccupying a position near the periphery of the nucleus. A

number of years ago it was proposed that compartmentalization might be an early event in X inactivation, helpintarget various repressivefactors thatmodify the inactive XThis idea was based on the observation that the inactive Xin somatic cell hybrids is relatively unstable and does noform a normal sex chromatin structure, suggesting that thinactive X does not occupy its traditional compartmenwithinthe nucleus. More recently it has been shown by higvoltage electron microscopy and microscopic analysis of protein (perichromin) normally covering chromosomes amitosis, but presenton the inactive X at interphase,that thsex chromatin has unique structural properties (Gartleet al., 1992). As mentioned earlier, late replication migh

signal this compartmentalization.How the inactivation signal spreads must also involv

XIST. Since XIST RNA does not contact DNA, it seemlikely that an RNAprotein interaction might be involvein stabilization and propagation of the signal. It has beeproposed that specific sequences along the X-chromosomcould play an important role in signal spread, andrecently, long interspersed repetitive sequence element(LINEs), which are present in an unusually high concentration on the X,have been proposed as a candidate(Lyon1998). LINEs occur throughout the genome, perhapaccounting for the fact that autosomal genes can binactivated in X:autosome translocations. Moreove

LINEs vary subtly in sequence from one locus to anotherpossibly accounting for the fact that some loci on the Xchromosome escape X inactivation; such regions masimply lack the appropriate LINE sequence. However, thRNAprotein interaction may be all that is necessary fothe accumulation and spread of XIST RNA along thchromosome.

How is the X-inactivation pattern maintained? Severaobservations on transformed cells indicate that if the XISlocus is deleted after X inactivation has occurred, the Xinactivation pattern is maintained. This is not surprisingas we know that a complex of repressive factors distinguisthe inactive from the active X, and that promote

methylation, for one, can maintain the X-inactivatiopatternin the absence of functioning XIST RNA. What wdo not know is whether XIST is able to maintaiinactivation in the absence of methylation or ancombination of the other repressive factors.




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Perspective

During the first 20 years after the X-inactivation model wasproposed, late replication and sex chromatin were the onlyphysical features known to distinguish the two Xs.Methylation differences were detected in the 1980s andfor a time it was believed to be the key process. XIST as a

single explanation of X inactivation promised a solution inthe1990s,only to bemodified bythe more recent reports onhistone acetylation differences between the two Xs. As thisentry was being written, the first report of a protein(mH2a1) preferentially associated with the inactive Xappeared. It is likely that that report is merely the firstassociating proteins with the inactivation process.

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