X-Chromosome Inactivation: A Crossroads Between Chromosome Architecture and Gene Regulation

2018 ◽  
Vol 52 (1) ◽  
pp. 535-566 ◽  
Author(s):  
Rafael Galupa ◽  
Edith Heard
Keyword(s):  
X Chromosome ◽  
Current Knowledge ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Female Development ◽  
Barr Body ◽  
Chromosome Conformation ◽  
X Chromosomes ◽  
Chromosome Architecture ◽  
Inactive X Chromosome

In somatic nuclei of female therian mammals, the two X chromosomes display very different chromatin states: One X is typically euchromatic and transcriptionally active, and the other is mostly silent and forms a cytologically detectable heterochromatic structure termed the Barr body. These differences, which arise during female development as a result of X-chromosome inactivation (XCI), have been the focus of research for many decades. Initial approaches to define the structure of the inactive X chromosome (Xi) and its relationship to gene expression mainly involved microscopy-based approaches. More recently, with the advent of genomic techniques such as chromosome conformation capture, molecular details of the structure and expression of the Xi have been revealed. Here, we review our current knowledge of the 3D organization of the mammalian X-chromosome chromatin and discuss its relationship with gene activity in light of the initiation, spreading, and maintenance of XCI, as well as escape from gene silencing.

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

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.

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

2005 ◽  
Vol 25 (7) ◽  
pp. 2757-2769 ◽  
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.

scholarly journals Contribution of epigenetic changes to escape from X-chromosome inactivation

2021 ◽  
Author(s):  
Bradley P. Balaton ◽  
Carolyn J. Brown
Keyword(s):  
Dna Methylation ◽  
X Chromosome ◽  
Cpg Islands ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Epigenetic Marks ◽  
Inactive X Chromosome ◽  
Gene Level ◽  
Allelic Differences

AbstractBackgroundX-chromosome inactivation (XCI) is the epigenetic inactivation of one of two X chromosomes in XX eutherian mammals. The facultatively heterochromatic inactive X chromosome acquires many chromatin changes including DNA methylation and histone modifications. Despite these changes, some genes escape or variably escape from inactivation, and to the extent that they have been studied, epigenetic marks correlate with expression.ResultsWe downloaded data from the International Human Epigenome Consortium and compared previous XCI status calls to DNA methylation, H3K4me1, H3K4me3, H3K9me3, H3K27ac, H3K27me3 and H3K36me3. At genes subject to XCI we found heterochromatic marks enriched, and euchromatic marks depleted on the inactive X when compared to the active X. Similar results were seen for genes escaping XCI although with diminished effect with H3K27me3 being most enriched. Using sample-specific XCI status calls made using allelic expression or DNA methylation we also compared differences between samples with opposite XCI statuses at variably escaping genes. We found some marks significantly differed with XCI status, but which marks were significant was not consistent between genes. We trained a model to predict XCI status from these epigenetic marks and obtained over 75% accuracy for genes escaping and over 90% for genes subject to XCI. This model allowed us to make novel XCI status calls for genes without allelic differences or CpG islands required for other XCI status calling methods. Using these calls to examine a domain of variably escaping genes, we saw XCI status vary at the level of individual genes and not at the domain level.ConclusionHere we show that epigenetic marks differ between genes that are escaping and those subject to XCI, and that genes escaping XCI still differ between the active and inactive Xs. We show epigenetic differences at variably escaping genes, between samples escaping and those subject to XCI. Lastly we show gene-level regulation of variably escaping genes within a domain.

scholarly journals Species-specific differences in X chromosome inactivation in mammals

Reproduction ◽  
2013 ◽  
Vol 146 (4) ◽  
pp. R131-R139 ◽  
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.

X-chromosome deletions in embryo-derived (EK) cell lines associated with lack of X-chromosome inactivation

Development ◽  
1985 ◽  
Vol 90 (1) ◽  
pp. 379-388
Author(s):  
Sohaila Rastan ◽  
Elizabeth J. Robertson
Keyword(s):  
Cell Lines ◽  
X Chromosome ◽  
Cytogenetic Study ◽  
Diploid Cell ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Metaphase Chromosomes ◽  
X Chromosomes ◽  
Inactive X Chromosome ◽  
Stem Cell Lines

The predictions of a model for the initiation of X-chromosome inactivation based on a single inactivation centre were tested in a cytogenetic study using six different embryo-derived (EK) stem cell lines, each with a different-sized deletion of the distal part of one of the X-chromosomes. Metaphase chromosomes were prepared by the Kanda method from each cell line in the undifferentiated state and after induction of differentiation, and cytogenetic evidence sought for a dark-staining inactive X-chromosome. The results confirm the predictions of the model in that when the inactivation centre is deleted from one of the X-chromosomes neither X present in a diploid cell can be inactivated, and in addition considerably further localize the position of the inactivation centre on the X-chromosome.

scholarly journals X-chromosome inactivation: dosage compensation of genes or heterochromatin?

2019 ◽  
pp. 75-87
Author(s):  
AI Ibraimov
Keyword(s):  
X Chromosome ◽  
Dosage Compensation ◽  
Sex Chromosome ◽  
Gene Dosage ◽  
Alternative Hypothesis ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Inactive X Chromosome ◽  
Mammalian Female

X-chromosome inactivation (XCI) is the process by which one of two X chromosomes in mammalian female cells is inactivated. The DNA of the inactive X chromosome is packaged in transcriptionally inactive heterochromatin. It is generally accepted that XCI have evolved to enable dosage compensation in mammals as a way to equalize X-linked gene expression between XX and XY individuals. However, there remain several controversial issues regarding the causes of XCI. The most important of them, why dosage compensation of genes? An alternative hypothesis is discussed that XCI is caused by dose compensation for heterochromatin, rather than genes, in the genome of female mammals due to the lack of a sex chromosome in their karyotype with a large constitutive heterochromatin block, as in Y chromosome in males. It is for this reason that heterochromatinization of the euchromatin regions of one of the X chromosomes occurs. The biological meaning of heterochromatinization is to increase the density of condensed chromatin (??) around the interphase nucleus, responsible for removing excess heat from the nucleus into the cytoplasm, since the compaction of ?? depends on the amount of heterochromatin. The consequence of this process is the inactivation of genes that were in the area of heterochromatinization of the X chromosome. Keywords: X-chromosome inactivation; Lyonization; Gene dosage compensation; Heterochromatin dosage compensation; Cell thermoregulation

X-chromosome reactivation: a concise review

2021 ◽  
Author(s):  
Alessandra Spaziano ◽  
Dr Irene Cantone
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Epigenetic Modifications ◽  
X Chromosomes ◽  
Cell Divisions ◽  
Concise Review ◽  
Inactive X Chromosome ◽  
Silencing Pathways

Mammalian females (XX) silence transcription on one of the two X chromosomes to compensate the expression dosage with males (XY). This process — named X-chromosome inactivation — entails a variety of epigenetic modifications that act synergistically to maintain silencing and make it heritable through cell divisions. Genes along the inactive X chromosome are, indeed, refractory to reactivation. Nonetheless, X-chromosome reactivation can occur alongside with epigenome reprogramming or by perturbing multiple silencing pathways. Here we review the events associated with X-chromosome reactivation during in vivo and in vitro reprogramming and highlight recent efforts in inducing Xi reactivation by molecular perturbations. This provides us with a first understanding of the mechanisms underlying X-chromosome reactivation, which could be tackled for therapeutic purposes.

Random X-chromosome inactivation in female primordial germ cells in the mouse

Development ◽  
1981 ◽  
Vol 64 (1) ◽  
pp. 251-258
Author(s):  
Andy McMahon ◽  
Mandy Fosten ◽  
Marilyn Monk
Keyword(s):  
X Chromosome ◽  
Germ Cells ◽  
Germ Line ◽  
Primordial Germ Cells ◽  
Phosphoglycerate Kinase ◽  
X Chromosome Inactivation ◽  
Yolk Sac ◽  
Chromosome Inactivation ◽  
X Chromosomes

The pattern of expression of the two X chromosomes was investigated in pre-meiotic germ cells from 12½-day-old female embryos heterozygous for the variant electrophoretic forms of the X-linked enzyme phosphoglycerate kinase (PGK-1). If such germ cells carry the preferentially active Searle's translocated X chromosome (Lyon, Searle, Ford & Ohno, 1964), then only the Pgk-1 allele on this chromosome is expressed. This confirms Johnston's evidence (1979,1981) that Pgk-1 expression reflects a single active X chromosome at this time. Extracts of 12½-day germ cells from heterozygous females carrying two normal X chromosomes show both the A and the B forms of PGK; since only one X chromosome in each cell is active, different alleles must be expressed in different cells, suggesting that X-chromosome inactivation is normally random in the germ line. This result makes it unlikely that germ cells are derived from the yolk-sac endoderm where the paternally derived X chromosome is preferentially inactivated. In their pattern of X-chromosome inactivation, germ cells evidently resemble other tissues derived from the epiblast.

Regulation of imprinted X-chromosome inactivation in mice by Tsix

Development ◽  
2001 ◽  
Vol 128 (8) ◽  
pp. 1275-1286 ◽  
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.

scholarly journals Localized accumulation of Xist RNA in X chromosome inactivation

Open Biology ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 190213 ◽  
Author(s):  
Neil Brockdorff
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Non Coding Rna ◽  
Xist Rna ◽  
Analogous Manner ◽  
Mammalian Embryos ◽  
Non Coding Rnas ◽  
In Cis

The non-coding RNA Xist regulates the process of X chromosome inactivation, in which one of the two X chromosomes present in cells of early female mammalian embryos is selectively and coordinately shut down. Remarkably Xist RNA functions in cis , affecting only the chromosome from which it is transcribed. This feature is attributable to the unique propensity of Xist RNA to accumulate over the territory of the chromosome on which it is synthesized, contrasting with the majority of RNAs that are rapidly exported out of the cell nucleus. In this review I provide an overview of the progress that has been made towards understanding localized accumulation of Xist RNA, drawing attention to evidence that some other non-coding RNAs probably function in a highly analogous manner. I describe a simple model for localized accumulation of Xist RNA and discuss key unresolved questions that need to be addressed in future studies.

Sign in / Sign up

Export Citation Format

Share Document