X chromosome inactivation in a female carrier of a 1.28 Mb deletion encompassing the human X inactivation centre

X chromosome inactivation (XCI) is a mechanism specifically initiated in female cells to silence one X chromosome, thereby equalizing the dose of X-linked gene products between male and female cells. XCI is regulated by a locus on the X chromosome termed the X-inactivation centre (XIC). Located within the XIC is XIST , which acts as a master regulator of XCI. During XCI, XIST is upregulated on the inactive X chromosome and chromosome-wide cis spreading of XIST leads to inactivation. In mouse, the Xic comprises Xist and all cis -regulatory elements and genes involved in Xist regulation. The activity of the XIC is regulated by trans -acting factors located elsewhere in the genome: X-encoded XCI activators positively regulating XCI, and autosomally encoded XCI inhibitors providing the threshold for XCI initiation. Whether human XCI is regulated through a similar mechanism, involving trans -regulatory factors acting on the XIC has remained elusive so far. Here, we describe a female individual with ovarian dysgenesis and a small X chromosomal deletion of the XIC. SNP-array and targeted locus amplification (TLA) analysis defined the deletion to a 1.28 megabase region, including XIST and all elements and genes that perform cis -regulatory functions in mouse XCI. Cells carrying this deletion still initiate XCI on the unaffected X chromosome, indicating that XCI can be initiated in the presence of only one XIC. Our results indicate that the trans -acting factors required for XCI initiation are located outside the deletion, providing evidence that the regulatory mechanisms of XCI are conserved between mouse and human. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.

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Getting to the center of X-chromosome inactivation: the role of transgenesThis paper is one of a selection of papers published in this Special Issue, entitled 30th Annual International Asilomar Chromatin and Chromosomes Conference, and has undergone the Journal’s usual peer review process.

Biochemistry and Cell Biology ◽

10.1139/o09-040 ◽

2009 ◽

Vol 87 (5) ◽

pp. 759-766 ◽

Cited By ~ 3

Author(s):

Jakub Minks ◽

Carolyn J. Brown

Keyword(s):

X Chromosome ◽

Peer Review Process ◽

Regulatory Elements ◽

X Chromosome Inactivation ◽

X Inactivation ◽

Chromosome Inactivation ◽

Xist Expression ◽

Inactivation Center ◽

Xist Rna ◽

Epigenetic Phenomenon

X-chromosome inactivation is a fascinating epigenetic phenomenon that is initiated by expression of a noncoding (nc)RNA, XIST, and results in transcriptional silencing of 1 female X. The process requires a series of events that begins even before XIST expression, and culminates in an active and a silent X within the same nucleus. We will focus on the role that transgenic systems have served in the current understanding of the process of X-chromosome inactivation, both in the initial delineation of an active and inactive X, and in the function of the XIST RNA. X inactivation is strictly cis-limited; recent studies have revealed elements within the X-inactivation center, the region required for inactivation, that are critical for the initial regulation of Xist expression and chromosome pairing. It has been revealed that the X-inactivation center contains a remarkable compendium of cis-regulatory elements, ncRNAs, and trans-acting pairing regions. We review the functional componentry of the X-inactivation center and discuss experiments that helped to dissect the XIST/Xist RNA and its involvement in the establishment of facultative heterochromatin.

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When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0355 ◽

2017 ◽

Vol 372 (1733) ◽

pp. 20160355 ◽

Cited By ~ 30

Author(s):

Laura Carrel ◽

Carolyn J. Brown

Keyword(s):

X Chromosome ◽

X Chromosome Inactivation ◽

X Inactivation ◽

Chromosome Inactivation ◽

Sequencing Technologies ◽

Inactive X Chromosome ◽

Underlying Basis ◽

Inactivation Process ◽

Escape From X Inactivation ◽

Mary Lyon

A tribute to Mary Lyon was held in October 2016. Many remarked about Lyon's foresight regarding many intricacies of the X-chromosome inactivation process. One such example is that a year after her original 1961 hypothesis she proposed that genes with Y homologues should escape from X inactivation to achieve dosage compensation between males and females. Fifty-five years later we have learned many details about these escapees that we attempt to summarize in this review, with a particular focus on recent findings. We now know that escapees are not rare, particularly on the human X, and that most lack functionally equivalent Y homologues, leading to their increasingly recognized role in sexually dimorphic traits. Newer sequencing technologies have expanded profiling of primary tissues that will better enable connections to sex-biased disorders as well as provide additional insights into the X-inactivation process. Chromosome organization, nuclear location and chromatin environments distinguish escapees from other X-inactivated genes. Nevertheless, several big questions remain, including what dictates their distinct epigenetic environment, the underlying basis of species differences in escapee regulation, how different classes of escapees are distinguished, and the roles that local sequences and chromosome ultrastructure play in escapee regulation. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.

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Identification of Developmentally Specific Enhancers for Tsix in the Regulation of X Chromosome Inactivation

Molecular and Cellular Biology ◽

10.1128/mcb.25.7.2757-2769.2005 ◽

2005 ◽

Vol 25 (7) ◽

pp. 2757-2769 ◽

Cited By ~ 55

Author(s):

Nicholas Stavropoulos ◽

Rebecca K. Rowntree ◽

Jeannie T. Lee

Keyword(s):

X Chromosome ◽

Regulatory Elements ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

X Chromosomes ◽

Binary Switch ◽

Inactive X Chromosome ◽

The Future ◽

Hypersensitive Sites ◽

Mammalian Female

ABSTRACT X chromosome inactivation silences one of two X chromosomes in the mammalian female cell and is controlled by a binary switch that involves interactions between Xist and Tsix, a sense-antisense pair of noncoding genes. On the future active X chromosome, Tsix expression suppresses Xist upregulation, while on the future inactive X chromosome, Tsix repression is required for Xist-mediated chromosome silencing. Thus, understanding the binary switch mechanism depends on ascertaining how Tsix expression is regulated. Here we have taken an unbiased approach toward identifying Tsix regulatory elements within the X chromosome inactivation center. First, we defined the major Tsix promoter and found that it cannot fully recapitulate the developmental dynamics of Tsix expression, indicating a requirement for additional regulatory elements. We then delineated two enhancers, one classical enhancer mapping upstream of Tsix and a bipartite enhancer that flanks the major Tsix promoter. These experiments revealed the intergenic transcription element Xite as an enhancer of Tsix and the repeat element DXPas34 as a component of the bipartite enhancer. Each enhancer contains DNase I-hypersensitive sites and appears to confer developmental specificity to Tsix expression. Characterization of these enhancers will facilitate the identification of trans-acting regulatory factors for X chromosome counting and choice.

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Species-specific differences in X chromosome inactivation in mammals

Reproduction ◽

10.1530/rep-13-0173 ◽

2013 ◽

Vol 146 (4) ◽

pp. R131-R139 ◽

Cited By ~ 18

Author(s):

Takashi Sado ◽

Takehisa Sakaguchi

Keyword(s):

X Chromosome ◽

Molecular Basis ◽

Embryonic Stem ◽

X Chromosome Inactivation ◽

X Inactivation ◽

Chromosome Inactivation ◽

X Chromosomes ◽

Inactive X Chromosome ◽

Species Specific ◽

Genetically Manipulated

In female mammals, the dosage difference in X-linked genes between XX females and XY males is compensated for by inactivating one of the two X chromosomes during early development. Since the discovery of the X inactive-specific transcript (XIST) gene in humans and its subsequent isolation of the mouse homolog, Xist, in the early 1990s, the molecular basis of X chromosome inactivation (X-inactivation) has been more fully elucidated using genetically manipulated mouse embryos and embryonic stem cells. Studies on X-inactivation in other mammals, although limited when compared with those in the mice, have revealed that, while their inactive X chromosome shares many features with those in the mice, there are marked differences in not only some epigenetic modifications of the inactive X chromosome but also when and how X-inactivation is initiated during early embryonic development. Such differences raise the issue about what extent of the molecular basis of X-inactivation in the mice is commonly shared among others. Recognizing similarities and differences in X-inactivation among mammals may provide further insight into our understanding of not only the evolutionary but also the molecular aspects for the mechanism of X-inactivation. Here, we reviewed species-specific differences in X-inactivation and discussed what these differences may reveal.

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Timing of X-chromosome inactivation in postimplantation mouse embryos

Development ◽

10.1242/dev.71.1.11 ◽

1982 ◽

Vol 71 (1) ◽

pp. 11-24

Author(s):

Sohaila Rastan

Keyword(s):

X Chromosome ◽

Mouse Embryo ◽

Female Mouse ◽

Primitive Streak ◽

X Chromosome Inactivation ◽

Mouse Embryos ◽

X Inactivation ◽

Chromosome Inactivation ◽

Inactive X Chromosome ◽

Dark Staining

The onset of X-chromosome inactivation was investigated cytologically in postimplantation female mouse embryos of age 5½, 6½ and 7½ days post-coitum (d.p.c.) and in the isolated epiblasts of 6 d.p.c. embryos before primitive streak formation using a heat/hypotonic technique to reveal the inactive X chromosome by differentially dark staining with Giemsa. The results indicate that X inactivation has taken place in all the cells of the so-called ‘undifferentiated’ epiblast by 6 d.p.c. before primitive streak formation. Further evidence is presented to suggest that X inactivation is complete in all cells of the mouse embryo by 5½ d.p.c.

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Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22031114 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1114

Author(s):

Ali Youness ◽

Charles-Henry Miquel ◽

Jean-Charles Guéry

Keyword(s):

Autoimmune Diseases ◽

X Chromosome ◽

Gene Dosage ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

X Chromosomes ◽

Female Sex Hormones ◽

Inactive X Chromosome ◽

Immune Related Genes ◽

Female Specific

Women represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system, recent data suggest that female sex hormones are not the only cause of the female predisposition to autoimmunity. Besides sex steroid hormones, growing evidence points towards the role of X-linked genetic factors. In female mammals, one of the two X chromosomes is randomly inactivated during embryonic development, resulting in a cellular mosaicism, where about one-half of the cells in a given tissue express either the maternal X chromosome or the paternal one. X chromosome inactivation (XCI) is however not complete and 15 to 23% of genes from the inactive X chromosome (Xi) escape XCI, thereby contributing to the emergence of a female-specific heterogeneous population of cells with bi-allelic expression of some X-linked genes. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity still remains to be established, the cellular mosaicism resulting from XCI escape is likely to create a unique functional plasticity within female immune cells. Here, we review recent findings identifying key immune related genes that escape XCI and the relationship between gene dosage imbalance and functional responsiveness in female cells.

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X-chromosome inactivation in XX androgenetic mouse embryos surviving implantation

Development ◽

10.1242/dev.127.19.4137 ◽

2000 ◽

Vol 127 (19) ◽

pp. 4137-4145 ◽

Cited By ~ 4

Author(s):

I. Okamoto ◽

S. Tan ◽

N. Takagi

Keyword(s):

X Chromosome ◽

Ectopic Expression ◽

Blastocyst Stage ◽

X Chromosome Inactivation ◽

X Inactivation ◽

Chromosome Inactivation ◽

Current View ◽

Replication Banding ◽

Xist Rna ◽

Morula Stage

Using genetic and cytogenetic markers, we assessed early development and X-chromosome inactivation (X-inactivation) in XX mouse androgenones produced by pronuclear transfer. Contrary to the current view, XX androgenones are capable of surviving to embryonic day 7.5, achieving basically random X-inactivation in all tissues including those derived from the trophectoderm and primitive endoderm that are characterized by paternal X-activation in fertilized embryos. This finding supports the hypothesis that in fertilized female embryos, the maternal X chromosome remains active until the blastocyst stage because of a rigid imprint that prevents inactivation, whereas the paternal X chromosome is preferentially inactivated in extra-embryonic tissues owing to lack of such imprint. In spite of random X-inactivation in XX androgenones, FISH analyses revealed expression of stable Xist RNA from every X chromosome in XX and XY androgenonetic embryos from the four-cell to morula stage. Although the occurrence of inappropriate X-inactivation was further suggested by the finding that Xist continues ectopic expression in a proportion of cells from XX and XY androgenones at the blastocyst and the early egg cylinder stage, a replication banding study failed to provide positive evidence for inappropriate X-inactivation at E6. 5.

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Investigation of variability among mouse aggregation chimaeras and X-chromosome inactivation mosaics

Development ◽

10.1242/dev.84.1.309 ◽

1984 ◽

Vol 84 (1) ◽

pp. 309-329

Author(s):

John D. West ◽

Theodor Bücher ◽

Ingrid M. Linke ◽

Manfred Dünnwald

Keyword(s):

X Chromosome ◽

Phosphoglycerate Kinase ◽

X Chromosome Inactivation ◽

Yolk Sac ◽

X Inactivation ◽

Chromosome Inactivation ◽

Cell Populations ◽

Primitive Endoderm ◽

Female Progeny ◽

Positive Correlations

Mouse aggregation chimaeras were produced by aggregating C3H/HeH and C3H/HeHa—Pgk-1a/Ws embryos. At mid-term the proportions of the two cell populations in these conceptuses and the X-inactivation mosaic female progeny of C3H/HeH ♀ × C3H/HeHa—Pgk-1a/Ws ♂ matings were estimated using quantitative electrophoresis of phosphoglycerate kinase (PGK-1) allozymes. The percentage of PGK-1B was more variable in the foetus, amnion and yolk sac mesoderm of the chimaeras than in the corresponding tissues of the mosaic conceptuses. Positive correlations were found for the percentage of PGK-1B between these three primitive ectoderm tissues in both chimaeras and mosaics and between the two primitive endoderm tissues (yolk sac endoderm and parietal endoderm) of the chimaeras. There was no significant correlation between the primitive ectoderm and primitive endoderm tissues of the chimaeras. The results suggest that unequal allocation of cell populations to the primitive ectoderm and primitive endoderm considerably increases the variability among chimaeras but variation probably exists before this segregation occurs. The variation that arises before and at this allocation event is present before X-chromosome inactivation occurs in the primitive ectoderm lineage and explains why the proportions of the two cell populations are more variable among chimaeras than mosaics. Additional variation arises within the primitive ectoderm lineage, after X-inactivation. This variation may be greater in chimaeras than mosaics but the evidence is inconclusive. The results also have some bearing on the nature of the allocation of cells to the primitive ectoderm and primitive endoderm lineages and the timing of X-chromosome inactivation in the primitive ectoderm lineage.

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Regulation of imprinted X-chromosome inactivation in mice by Tsix

Development ◽

10.1242/dev.128.8.1275 ◽

2001 ◽

Vol 128 (8) ◽

pp. 1275-1286 ◽

Cited By ~ 5

Author(s):

T. Sado ◽

Z. Wang ◽

H. Sasaki ◽

E. Li

Keyword(s):

X Chromosome ◽

X Chromosome Inactivation ◽

X Inactivation ◽

Chromosome Inactivation ◽

Maternal Allele ◽

Xist Expression ◽

Developmental Defects ◽

X Chromosomes ◽

Embryonic Tissues ◽

Early Embryonic Lethality

In mammals, X-chromosome inactivation is imprinted in the extra-embryonic lineages with paternal X chromosome being preferentially inactivated. In this study, we investigate the role of Tsix, the antisense transcript from the Xist locus, in regulation of Xist expression and X-inactivation. We show that Tsix is transcribed from two putative promoters and its transcripts are processed. Expression of Tsix is first detected in blastocysts and is imprinted with only the maternal allele transcribed. The imprinted expression of Tsix persists in the extra-embryonic tissues after implantation, but is erased in embryonic tissues. To investigate the function of Tsix in X-inactivation, we disrupted Tsix by insertion of an IRES(β)geo cassette in the second exon, which blocked transcripts from both promoters. While disruption of the paternal Tsix allele has no adverse effects on embryonic development, inheritance of a disrupted maternal allele results in ectopic Xist expression and early embryonic lethality, owing to inactivation of both X chromosomes in females and single X chromosome in males. Further, early developmental defects of female embryos with maternal transmission of Tsix mutation can be rescued by paternal inheritance of the Xist deletion. These results provide genetic evidence that Tsix plays a crucial role in maintaining Xist silencing in cis and in regulation of imprinted X-inactivation in the extra-embryonic tissues.

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Persistence of skewed X-chromosome inactivation in pre-B acute lymphoblastic leukemia of a female ATRX mutation carrier

Blood Advances ◽

10.1182/bloodadvances.2019000013 ◽

2019 ◽

Vol 3 (17) ◽

pp. 2627-2631

Author(s):

Christian P. Bradley ◽

Cai Chen ◽

Karolyn A. Oetjen ◽

Cheng Yan ◽

Reema Panjwani ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

X Chromosome ◽

Germline Mutation ◽

Mutation Carrier ◽

Lymphoblastic Leukemia ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Female Carrier ◽

Key Points ◽

Skewed X Chromosome Inactivation

Key Points Leukemic blasts of a female carrier of an ATRX germline mutation have persistently skewed inactivation of the X chromosome. Germline mutation in leukemia needs to be interpreted with caution because it is not always pathologic.

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