Define x chromosome activation

However, outside of OR and antigen receptor genes, the importance of RMAE-driven phenotypic diversity remains to be demonstrated, and it is a complicated problem to tackle experimentally.

As explained below, particular cis -regulatory sequences play a role in RMAE. Thus, a feasible approach would be to replace these sequences with regular promoters, but even in this case the interpretation of the data would not be clear-cut because the expression of multiple receptors at the surface of the cell would decrease the density of any particular receptor compared to its density in a cell with RMAE.

An alternative approach would be to generate aggregation chimeras of cells expressing different receptors or other relevant proteins for the quantitative response to be tested. In the absence of such data, other hypotheses can be raised, such as a role for RMAE in dosage compensation Gendrel et al.

However, the finding that genes under RMAE have increased genetic diversity polymorphisms in humans compared to biallelically expressed genes remains a powerful indication that RMAE evolved to increase phenotypic diversity at the cellular level Savova et al. One has to recognize that stochasticity is the key feature common to XCI and RMAE: how come identical or quasi-identical sequences the X chromosomes or autosomal alleles sharing the same nuclear environment undergo completely opposite fates expression or silencing?

This stochastic component is at the core of the appeal these phenomena have to biologists, but there is a critical difference between XCI and RMAE worth mentioning. It has been proposed that each individual X chromosome has an independent probability to be inactivated that is directly proportional to the X: ploidy ratio.

Selection in favor of cells keeping one active X chromosome per diploid genome eliminates cells with two inactive X or two active X chromosomes Monkhorst et al. Thus, XCI involves the inactivation of one X chromosome and counterselection at the cellular level. In contrast, the stochastic component in OR genes, antigen receptor genes, and possibly other autosomal genes under RMAE involves the activation of alleles in a default state of silencing, and cell counterselection is not thought to play a major role in shaping the pattern of monoallelic expression; in fact, B lymphocytes genetically engineered to express two different immunoglobulin heavy chains at the surface were shown to be fit and able to generate a normal B cell compartment Sonoda et al.

A key aspect of RMAE in antigen receptor genes is the feedback mechanism that prevents the recombination of the second allele once the protein encoded by the first allele to rearrange productively is expressed at the surface. When the exon encoding the transmembrane domain of the immunoglobulin chain is disrupted, the cell is no longer able to trigger this feedback mechanism and the second allele is given the chance to recombine Kitamura and Rajewsky, A similar mechanism has been described for the beta chain of the TCR gene Aifantis et al.

The overall picture, then, is the coupling of a stochastic process of gene activation that is sufficiently slow for negative feedback mechanisms to act, preventing further rearrangements antigen receptors or gene activation OR genes. Because the feedback mechanism implies a time-window during which the two alleles can be activated, it also explains the generation of biallelic cells; a slow feedback mechanism will produce many biallelic cells, whereas biallelic cells are rare when the time-window is narrow.

However, it is not clear whether such feedbacks are involved for other genes under RMAE and additional mechanisms have been described, which we discuss below. The process of XCI can be divided in two distinct stages: initiation and maintenance. During the initiation phase, XCI is dependent on the expression of the long non-coding RNA Xist , which induces transcriptional silencing in cis and ultimately coats the entire inactive X chromosome Loda and Heard, However, Xist is no longer essential for the maintenance of XCI, as deletion of Xist in somatic cells in culture does not lead to Xi reactivation Brown and Willard, Following Xist accumulation on the Xi, one of the first observable events is the formation of a 3D silent nuclear compartment excluding RNA polymerase II and transcription factors, likely to be important for Xist spreading and the initiation of gene silencing Chaumeil et al.

Following this, a number of chromosome-wide chromatin changes occur on the Xi to lock in the silenced state, such as deposition of repressive histone modifications H2AKUb and H3K27me3 mediated by the Polycomb repressive complexes 1 and 2 [reviewed in Boeren and Gribnau ]. The late or maintenance phase is characterized by a switch to late replication timing, incorporation of the histone variant macroH2A and DNA methylation of X-linked gene promoter regions by the DNA methyltransferase Dnmt3b [reviewed in Strehle and Guttman ].

These changes ensure the stable and heritable silencing of the majority of genes on the Xi, over hundreds of cell divisions. However, unlike XCI, there is no master regulator, and several scenarios have been reported, such the initial repression of both alleles followed by activation e. One puzzling question in XCI has been the nature of the X-linked cis -acting elements important for the binding and spreading of Xist along the X chromosome, prior to gene silencing.

Because of the higher density of long interspersed nuclear element-1 LINE-1 retrotransposons in the X chromosome compared to autosomes Boyle et al. Xist rather exploits the 3D conformation of the X chromosome to spread first to sites that are spatially proximal to the Xist gene at the onset of XCI and is then found enriched over gene-dense regions that are depleted of LINE-1 sequences Engreitz et al.

Yet, studies of Xist spreading on autosomal chromatin in X:autosome translocations Sharp et al. This, however, remains to be formally tested using, for example, functional approaches to perturb LINE-1 expression or enrichment on the X chromosome. It has been proposed that these genes are surrounded by an increased density of LINE-1 elements, which are evolutionarily more recent and less truncated than the LINE-1 elements around biallelically expressed genes Allen et al. It has been known for decades that the X chromosome and autosomal genes under RMAE replicate asynchronously Taylor, ; Chess et al.

Asynchronous replication was even found to be a property of autosomal chromosomes Singh et al. Whether the asynchronous replication of autosomes is absolutely stable is not clear, and it has been found that RMAE is not coordinated at the chromosome level, i. However, an autosomal gene named asynchronous replication and autosomal RNA on chromosome 6 ASAR6 was shown to encode a non-coding RNA under RMAE, which when expressed leads to the silencing of nearby alleles and remains associated with the chromosome from which it is expressed.

Moreover, the disruption of this locus results in delayed replication timing and reactivation of previously silent alleles of nearby genes Stoffregen et al. There is an obvious parallel with XIST , which is also monoallelically expressed, silences most of the genes on the X chromosome in cis and, when deleted, also alters replication timing Diaz-Perez et al. This constitutes one of the most solid evidence that LINE-1 elements could be involved in the spreading of inactivation also on autosomal chromosomes.

However, it is not known how frequent this type of regional silencing occurs on autosomes, and, unlike XIST , the ASAR6 RNA does not seem to coat the entire chromosome 6 and is not expressed in adult tissues Stoffregen et al. Several histone modifications influence gene expression, including H3K4me3 and H3K27me3, which are associated with gene activation and repression, respectively. Although active and repressive histone marks are typically imagined as being mutually exclusive, in two groups reported the existence of regulatory regions — named bivalent domains — that have both Azuara et al.

Genes with bivalent promoters in embryonic stem cells are expressed at low levels but thought to be poised for rapid activation upon differentiation cues. Thus, the rapid and timely activation ensured by bivalent promoters seems to increase the probability of RMAE, as if the alleles resolve their status stochastically, leading to cells that activate only the paternal or maternal allele and cells that activate both Nag et al.

A schematic representation of mechanisms responsible for X-chromosome inactivation XCI and mechanisms possibly responsible for random monoallelic autosomal expression RMAE. Both rely on cis probabilistic bidirectional promoter switches that produce sense and antisense transcripts associated with expression and silencing, respectively Figure 2.

In the case of the murine Ly49 receptor genes, the default condition is silencing. Transcription starts if the sense non-coding transcripts of a distal bidirectional promoter Pro1 activate a downstream promoter Pro2 ; the antisense transcripts of the bidirectional promoter do not lead to gene activation Saleh et al. In the case of the KIR genes, the default condition is activation and the role of the stochastic switch, located close to the ATG start codon, is to produce a sense transcript that correlates with the maintenance of the activation state or an antisense piRNA that silences the allele.

The murine Ly49 and the human KIR genes illustrate how a probabilistic bidirectional promoter can create a mitotically stable asymmetry between two alleles. Whether these are two exceptional cases or examples of a frequent solution to generate RMAE has not been addressed. Once established, XCI is believed to be extremely stable and irreversible. Genes that are subject to XCI rarely show reactivation and biallelic expression, as silencing is maintained through multiple layers of epigenetic control.

However, there are some exceptions and some genes can be expressed from both the Xa and the Xi. This is the case for genes that have a Y-linked homolog, including genes from the pseudoautosomal regions PAR1 and PAR2, short regions of homology between the X and Y chromosomes, which undergo recombination during meiosis , for which there is no requirement for dosage compensation. Several genes not located in the PAR regions have also retained a functional Y paralog and would thus appear not to require dosage compensation.

However, other genes do not have a Y-linked copy yet still have the ability to escape XCI Berletch et al. In some cases, this may be due to a highly controlled process permitting escape where the gene product is required in increased dose, while in other cases, it may be due to leaky or inefficient XCI.

Such candidates seem to display accessible promoter regions on the Xi Kucera et al. In the mouse, lineage-specific escape has also been found, for example in the case of the Atrx gene, which is fully inactivated in embryonic tissues but escapes inactivation in specific subsets of extraembryonic cells Garrick et al.

Interestingly, some of the phenotypes observed in Turner X0 syndrome patients are believed to be due, in part, to the reduced expression levels of escapees given the lack of the second X chromosome Berletch et al.

This indicates that expression of a double dose is essential for some X-linked genes and that escape for these genes is a highly controlled process. Escape or reactivation of genes from the Xi can also occur more sporadically, but it is currently unknown whether this is caused by inefficient XCI or associated with a controlled mechanism. Sporadic reactivation of genes from the Xi has been observed in non-pathological contexts, in specific tissues Gendrel et al.

In normal contexts, both the brain and the lymphoid lineage appear to stand as exceptions. In the brain, the Mecp2 gene, which is associated with Rett syndrome, was shown to display biallelic expression in a significant proportion of neural stem cells in the subventricular zone in the neonatal brain of inbred female mice Gendrel et al.

This could be indicative of a certain relaxation of epigenetic control of the Xi in these cells at least for this gene or a need for an increased dose of the protein, given that MeCP2 is a highly abundant protein in the brain Skene et al.

Other studies have also reported partial Xi reactivation following Xist conditional deletion in adult tissues Yildirim et al. In the female lymphoid lineage, the maintenance of XCI is atypical and it has been hypothesized that this could predispose females to autoimmunity Wang et al. Instead, Xist shows an unusual and dispersed pattern, associated with a structure lacking some of the canonical hallmarks of heterochromatin of the Xi, such as H3K27me3, H2AKub1 and macroH2A.

This state was shown to be correlated with modest biallelic expression and increased expression of X-linked immunity-related genes Wang et al. However, enhanced expression of these genes could contribute to higher susceptibility of females to autoimmune disorders, such as systemic lupus erythematosus if not properly regulated Youness et al. Concerning RMAE, by definition all the examples of monoallelic expression discovered in clonal cell lines are mitotically stable.

However, most reports have focused on cells that are also phenotypically stable, i. Thus, it remains to be addressed if RMAE is as stable as XCI, which is known to keep the status of the X chromosomes established early in development even after hundreds of cell divisions and extensive differentiation.

Unfortunately, the antigen receptor and OR genes, which have been thoroughly investigated over decades, do not shed much light on this issue. The monoallelic expression pattern of antigen receptor genes is in part established by the process of V D J recombination and in developing lymphocytes, when recombination is active, the second allele is given the chance to recombine if the rearrangement of the first allele did not lead to the production of a receptor.

In other words, the stability is not achieved before the expression of the receptor on the surface. Furthermore, the kappa immunoglobulin undergoes a process of receptor editing during which it can replace at its surface one protein by the protein encoded by the other allele Casellas et al.

It is only in mature lymphocytes that the pattern of monoallelic expression is stable, because the process of V D J recombination is permanently shut down and the silenced allele is epigenetically repressed and repositioned in the nucleus. With respect to OR genes, the patterns of monoallelic expression are stable, but it should be kept in mind that the cells are post-mitotic and terminally differentiated Monahan and Lomvardas, In mammalian females, under normal physiological conditions cases of two active X chromosomes are only found in undifferentiated cells and primordial germ cells before meiosis entry.

All other cells have only one active X chromosome, because the double X dosage interferes with differentiation Schulz et al. In contrast, biallelic expression of genes under RMAE is common and ranges from rare cells, such as in the case of the immunoglobulin heavy chain Barreto and Cumano, , to biallelic populations as frequent as the monoallelic ones Gimelbrant et al. In the case of genes under RMAE with a low frequency of biallelic expression, these exceptions could correspond to the rare cases in which the two alleles become activated within the time-window allowed, before a negative feedback is triggered.

Cases with a sizable population of biallelic expression could result from a relatively high individual probability of allele activation if the fitness of the cell is not compromised by the dual expression.

X-chromosome inactivation XCI is a well-established specific silencing mechanism that ensures dosage compensation between the sexes in marsupial and placental mammals.

At the heart of this process lies the long non-coding RNA Xist , which is capable of orchestrating structural changes and recruiting chromatin and repressor complexes to ensure transcriptional gene silencing at the level of an entire chromosome, early in development.

XCI has clear implications in disease, as illustrated by the Turner X0 and Klinefelter XXY syndromes, as well as the severe phenotypes or lethality in males and variable phenotypes in females associated with X-linked disorders e.

In contrast, RMAE evolved independently in a wide range of organisms beyond mammals, mostly to increase phenotypic diversity at the cellular level. RMAE lacks a master regulator and various mechanisms can establish it at different times during cellular differentiation.

The collection of target genes encompass many cell types, showing some degree of overlap Figure 3 and Supplementary File , but have been reported to be largely tissue-specific Gendrel et al. Finally, the extent of the bias in monoallelic expression varies widely amongst RMAE genes.

In addition, there is so far no obvious link between the RMAE of autosomal genes and disease, although a number of RMAE genes are associated with autosomal dominant diseases. X-chromosome inactivation and RMAE are essentially different phenomena that share the stochastic component and perhaps the asymmetric silencing of chromosomal regions dependent on the presence of LINE-1 elements.

Intersections of autosomal gene collections identified as random monoallelically expressed in the genome-wide studies described in Table 2 except Jeffries et al. A Half-matrix showing all pairwise intersections. B Upset plot Conway et al. The lower part of the panel has a horizontal bar plot showing the number of elements on each study collection, and a right section with a dot matrix. Each dot represents unique gene intersections, i. The upper vertical bar plot is related to the dot matrix, showing the number of unique genes in each intersection for instance, there are MAE genes in the Gimelbrant et al.

Intersections of size smaller than 4 are not represented. For a complete description of the intersections and gene listing, see the Supplementary File provided with this review. To obtain intersections, gene ids were manually curated for immediate inconsistencies e. All gene sets were then parsed with the gprofiler2 R package Raudvere et al. Orthology conversion from human to mouse was performed with the same package for datasets involving human data. For Gimelbrant et al.

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Published online Sep Vasco M. Clara F. Author information Article notes Copyright and License information Disclaimer. Barreto, tp. Anne-Valerie Gendrel, tp. This article was submitted to Developmental Epigenetics, a section of the journal Frontiers in Cell and Developmental Biology.

Received Jul 13; Accepted Aug The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.

No use, distribution or reproduction is permitted which does not comply with these terms. Abstract X-chromosome inactivation XCI and random monoallelic expression of autosomal genes RMAE are two paradigms of gene expression regulation where, at the single cell level, genes can be expressed from either the maternal or paternal alleles.

Keywords: X-chromosome inactivation, random monoallelic expression, epigenetic silencing, LINE-1 elements, cellular diversity, stochasticity, dosage compensation. Introduction In diploid organisms, the two alleles of a gene are usually expressed. TABLE 1 List of autosomal genes under random monoallelic expression reported in studies focused on single genes.

Open in a separate window. Timing XCI is initiated during early embryogenesis in mammals. Molecular Mechanisms Stochasticity One has to recognize that stochasticity is the key feature common to XCI and RMAE: how come identical or quasi-identical sequences the X chromosomes or autosomal alleles sharing the same nuclear environment undergo completely opposite fates expression or silencing?

Feedback A key aspect of RMAE in antigen receptor genes is the feedback mechanism that prevents the recombination of the second allele once the protein encoded by the first allele to rearrange productively is expressed at the surface. Epigenetics The process of XCI can be divided in two distinct stages: initiation and maintenance.

Long Interspersed Nuclear Element-1 One puzzling question in XCI has been the nature of the X-linked cis -acting elements important for the binding and spreading of Xist along the X chromosome, prior to gene silencing. Bivalent Promoters Several histone modifications influence gene expression, including H3K4me3 and H3K27me3, which are associated with gene activation and repression, respectively. Stability Once established, XCI is believed to be extremely stable and irreversible. Exceptions In mammalian females, under normal physiological conditions cases of two active X chromosomes are only found in undifferentiated cells and primordial germ cells before meiosis entry.

Concluding Remarks X-chromosome inactivation XCI is a well-established specific silencing mechanism that ensures dosage compensation between the sexes in marsupial and placental mammals. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments We thank the reviewers for providing constructive comments to this review. References Adegbola A. Monoallelic expression of the human FOXP2 speech gene. Perturbed maintenance of transcriptional repression on the inactive X-chromosome in the mouse brain after Xist deletion. Epigenetics Chromatin 11 : Essential role of the pre-T cell receptor in allelic exclusion of the T cell receptor beta locus. Immunity 7 — And the normal gene is almost always allowed to stay on.

In X-linked diseases in males, of course, X-linked diseases manifest because they only have one X chromosome, and so those mutated genes have to show up. But the fascinating part about it, which we really don't understand, is how it is that the body knows if the female inherits one copy of a gene that is abnormal and would otherwise cause an X-linked disease if the normal copy was lyonized and turned off. That doesn't happen.

The abnormal copy gets turned off, leaving the normal copy to function, and saving the female from having the disease. Christopher P. Changes in adjacent genes may account for some of the other signs and symptoms, such as neurological abnormalities and unusual facial features, that occur in some affected individuals. Klinefelter syndrome is a chromosomal condition in males that can affect physical and intellectual development. It is caused by an extra copy of the X chromosome.

Males with Klinefelter syndrome have the usual single Y chromosome plus two copies of the X chromosome, for a total of 47 chromosomes in each cell 47,XXY. Having an extra copy of genes on the X chromosome affects many aspects of development, including sexual development before birth and at puberty.

Researchers are working to determine which genes contribute to the specific developmental and physical differences that can occur with Klinefelter syndrome. Some people with features of Klinefelter syndrome have an extra X chromosome in only some of their cells; other cells have one X and one Y chromosome.

Males with mosaic Klinefelter syndrome may have milder signs and symptoms than those with the extra X chromosome in all of their cells, depending on what proportion of cells have the additional chromosome.

Several conditions resulting from the presence of more than one extra sex chromosome in each cell are sometimes described as variants of Klinefelter syndrome. The features of these disorders tend to be more severe than those of Klinefelter syndrome and affect more parts of the body.

A deletion of genetic material in a region of the X chromosome called Xp22 causes microphthalmia with linear skin defects syndrome. This condition is characterized by small or poorly developed eyes microphthalmia and unusual linear skin markings on the head and neck. The Xp22 region includes a gene called HCCS , which carries instructions for producing an enzyme called holocytochrome c-type synthase.

This enzyme helps produce a molecule called cytochrome c. Cytochrome c is involved in a process called oxidative phosphorylation, by which mitochondria generate adenosine triphosphate ATP , the cell's main energy source.

It also plays a role in the self-destruction of cells apoptosis. A deletion of genetic material that includes the HCCS gene prevents the production of the holocytochrome c-type synthase enzyme. In females who have two X chromosomes , some cells produce a normal amount of the enzyme and other cells produce none. The resulting overall reduction in the amount of this enzyme leads to the signs and symptoms of microphthalmia with linear skin defects syndrome. In males who have only one X chromosome , a deletion that includes the HCCS gene results in a total loss of the holocytochrome c-type synthase enzyme.

A lack of this enzyme appears to be lethal very early in development, so almost no males are born with microphthalmia with linear skin defects syndrome. A few affected individuals with male appearance who have two X chromosomes have been identified.

A reduced amount of the holocytochrome c-type synthase enzyme can damage cells by impairing their ability to generate energy. In addition, without the holocytochrome c-type synthase enzyme, the damaged cells may not be able to undergo apoptosis. These cells may instead die in a process called necrosis that causes inflammation and damages neighboring cells. During early development this spreading cell damage may lead to the eye and skin abnormalities characteristic of microphthalmia with linear skin defects syndrome.

Triple X syndrome also called 47,XXX or trisomy X results from an extra copy of the X chromosome in each of a female's cells. Females with triple X syndrome have three X chromosomes, for a total of 47 chromosomes per cell. An extra copy of the X chromosome can be associated with tall stature, developmental delays, learning problems, and other features in some females.

Some females with triple X syndrome have an extra X chromosome in only some of their cells. As the number of extra sex chromosomes increases, so does the risk of learning problems, intellectual disability, birth defects, and other health issues. Turner syndrome results when one normal X chromosome is present in a female's cells and the other sex chromosome is missing or structurally altered. The missing genetic material affects development before and after birth, leading to short stature, ovarian malfunction, and other features of Turner syndrome.

About half of individuals with Turner syndrome have monosomy X 45,X , which means each cell in an individual's body has only one copy of the X chromosome instead of the usual two sex chromosomes.

Turner syndrome can also occur if one of the sex chromosomes is partially missing or rearranged rather than completely absent. Some females with Turner syndrome have a chromosomal change in only some of their cells, which is known as mosaicism. Some cells have the usual two sex chromosomes either two X chromosomes or one X chromosome and one Y chromosome , and other cells have only one copy of the X chromosome.

Researchers have not determined which genes on the X chromosome are responsible for most of the features of Turner syndrome. They have, however, identified one gene called SHOX that is important for bone development and growth. The SHOX gene is located in the pseudoautosomal regions of the sex chromosomes. Missing one copy of this gene likely causes short stature and skeletal abnormalities in females with Turner syndrome. Duplication of a small amount of genetic material on the X chromosome causes X-linked acrogigantism X-LAG , which is characterized by abnormally fast growth beginning in infancy or early childhood.

Affected individuals may have the condition as a result of enlargement hyperplasia of the pituitary gland or development of a noncancerous tumor in the gland called a pituitary adenoma. The pituitary is a small gland at the base of the brain that produces hormones that control many important body functions, including growth hormone, which helps direct growth of the body.

The abnormal gland releases more growth hormone than normal, causing rapid growth in individuals with X-LAG. The duplication, often referred to as an Xq The GPR gene provides instructions for making a protein whose function is unknown, although it is thought to be involved in the growth of cells in the pituitary gland or in the release of growth hormone from the gland.

It is unclear how extra GPR protein results in the development of a pituitary adenoma or hyperplasia or in the release of excess growth hormone. Chromosomal conditions involving the sex chromosomes often affect sex determination whether a person has the sexual characteristics of a male or a female , sexual development, and the ability to have biological children fertility.