scholarly journals Conversion of random X-inactivation to imprinted X-inactivation by maternal PRC2

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Clair Harris ◽  
Marissa Cloutier ◽  
Megan Trotter ◽  
Michael Hinten ◽  
Srimonta Gayen ◽  
...  
Keyword(s):  
X Chromosome ◽  
Epigenetic Inheritance ◽  
X Inactivation ◽  
Human Embryos ◽  
Xist Expression ◽  
X Chromosomes ◽  
Polycomb Repressive Complex 2 ◽  
Early Embryos ◽  
Early Human

Imprinted X-inactivation silences genes exclusively on the paternally-inherited X-chromosome and is a paradigm of transgenerational epigenetic inheritance in mammals. Here, we test the role of maternal vs. zygotic Polycomb repressive complex 2 (PRC2) protein EED in orchestrating imprinted X-inactivation in mouse embryos. In maternal-null (Eedm-/-) but not zygotic-null (Eed-/-) early embryos, the maternal X-chromosome ectopically induced Xist and underwent inactivation. Eedm-/- females subsequently stochastically silenced Xist from one of the two X-chromosomes and displayed random X-inactivation. This effect was exacerbated in embryos lacking both maternal and zygotic EED (Eedmz-/-), suggesting that zygotic EED can also contribute to the onset of imprinted X-inactivation. Xist expression dynamics in Eedm-/- embryos resemble that of early human embryos, which lack oocyte-derived maternal PRC2 and only undergo random X-inactivation. Thus, expression of PRC2 in the oocyte and transmission of the gene products to the embryo may dictate the occurrence of imprinted X-inactivation in mammals.

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 Human Genes Escaping X-inactivation Revealed by Single Cell Expression Data

2018 ◽  
Author(s):  
Kerem Wainer Katsir ◽  
Michal Linial
Keyword(s):  
Single Cell ◽  
X Chromosome ◽  
Noncoding Rna ◽  
Phenotypic Variability ◽  
Cell Types ◽  
X Inactivation ◽  
Specific Expression ◽  
X Chromosomes ◽  
Human Genes ◽  
Cumulative Knowledge

AbstractBackgroundIn mammals, sex chromosomes pose an inherent imbalance of gene expression between sexes. In each female somatic cell, random inactivation of one of the X-chromosomes restores this balance. While most genes from the inactivated X-chromosome are silenced, 15-25% are known to escape X-inactivation (termed escapees). The expression levels of these genes are attributed to sex-dependent phenotypic variability.ResultsWe used single-cell RNA-Seq to detect escapees in somatic cells. As only one X-chromosome is inactivated in each cell, the origin of expression from the active or inactive chromosome can be determined from the variation of sequenced RNAs. We analyzed primary, healthy fibroblasts (n=104), and clonal lymphoblasts with sequenced parental genomes (n=25) by measuring the degree of allelic-specific expression (ASE) from heterozygous sites. We identified 24 and 49 candidate escapees, at varying degree of confidence, from the fibroblast and lymphoblast transcriptomes, respectively. We critically test the validity of escapee annotations by comparing our findings with a large collection of independent studies. We find that most genes (66%) from the unified set were previously reported as escapees. Furthermore, out of the overlooked escapees, 11 are long noncoding RNA (lncRNAs).ConclusionsX-chromosome inactivation and escaping from it are robust, permanent phenomena that are best studies at a single-cell resolution. The cumulative information from individual cells increases the potential of identifying escapees. Moreover, despite the use of a limited number of cells, clonal cells (i.e., same X-chromosomes are coordinately inhibited) with genomic phasing are valuable for detecting escapees at high confidence. Generalizing the method to uncharacterized genomic loci resulted in lncRNAs escapees which account for 20% of the listed candidates. By confirming genes as escapees and propose others as candidates from two different cell types, we contribute to the cumulative knowledge and reliability of human escapees.

scholarly journals X chromosome choice occurs independently of asynchronous replication timing

2005 ◽  
Vol 168 (3) ◽  
pp. 365-373 ◽  
Author(s):  
Joost Gribnau ◽  
Sandra Luikenhuis ◽  
Konrad Hochedlinger ◽  
Kim Monkhorst ◽  
Rudolf Jaenisch
Keyword(s):  
X Chromosome ◽  
Molecular Mechanisms ◽  
Replication Timing ◽  
S Phase ◽  
X Inactivation ◽  
Wild Type ◽  
Gene Deletions ◽  
Asynchronous Replication ◽  
Skewed X Inactivation

In mammals, dosage compensation is achieved by X chromosome inactivation in female cells. Xist is required and sufficient for X inactivation, and Xist gene deletions result in completely skewed X inactivation. In this work, we analyzed skewing of X inactivation in mice with an Xist deletion encompassing sequence 5 KB upstream of the promoter through exon 3. We found that this mutation results in primary nonrandom X inactivation in which the wild-type X chromosome is always chosen for inactivation. To understand the molecular mechanisms that affect choice, we analyzed the role of replication timing in X inactivation choice. We found that the two Xist alleles and all regions tested on the X chromosome replicate asynchronously before the start of X inactivation. However, analysis of replication timing in cell lines with skewed X inactivation showed no preference for one of the two Xist alleles to replicate early in S-phase before the onset of X inactivation, indicating that asynchronous replication timing does not play a role in skewing of X inactivation.

Molecular Characterization of Tiny Ring X Chromosomes from Females with Functional X Chromosome Disomy and Lack of cis X Inactivation

Genomics ◽  
1995 ◽  
Vol 27 (1) ◽  
pp. 182-188 ◽  
Author(s):  
Mihir M. Jani ◽  
Beth S. Torchia ◽  
G.Shashidhar Pai ◽  
Barbara R. Migeon
Keyword(s):  
Molecular Characterization ◽  
X Chromosome ◽  
X Inactivation ◽  
X Chromosomes

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.

2009 ◽  
Vol 87 (5) ◽  
pp. 759-766 ◽  
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.

scholarly journals Do LINEs Have a Role in X-Chromosome Inactivation?

2006 ◽  
Vol 2006 ◽  
pp. 1-6 ◽  
Author(s):  
Mary F. Lyon
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Current Evidence ◽  
X Chromosomes ◽  
Repeat Elements ◽  
Sequencing Project ◽  
Human Genome Sequencing ◽  
Human And Mouse

There is longstanding evidence that X-chromosome inactivation (XCI) travels less successfully in autosomal than in X-chromosomal chromatin. The interspersed repeat elements LINE1s (L1s) have been suggested as candidates for “boosters” which promote the spread of XCI in the X-chromosome. The present paper reviews the current evidence concerning the possible role of L1s in XCI. Recent evidence, accruing from the human genome sequencing project and other sources, confirms that mammalian X-chromosomes are indeed rich in L1s, except in regions where there are many genes escaping XCI. The density of L1s is the highest in the evolutionarily oldest regions. Recent work on X; autosome translocations in human and mouse suggested failure of stabilization of XCI in autosomal material, so that genes are reactivated, but resistance of autosomal genes to the original silencing is not excluded. The accumulation of L1s on the X-chromosome may have resulted from reduced recombination or late replication. Whether L1s are part of the mechanism of XCI or a result of it remains enigmatic.

scholarly journals Studies on Metatherian Sex Chromosomes III. The Use of Tritiated Uridine-induced Chromosome Aberrations to Distinguish Active and Inactive X Chromosomes

1977 ◽  
Vol 30 (2) ◽  
pp. 103 ◽  
Author(s):  
Jennifer A Donald ◽  
DW Cooper
Keyword(s):  
X Chromosome ◽  
Sex Chromosomes ◽  
Chromosome Aberrations ◽  
X Inactivation ◽  
Facultative Heterochromatin ◽  
Hybrid Female ◽  
X Chromosomes ◽  
Toxicity Effect ◽  
Red Kangaroo ◽  
Chromosome Regions

The paternal X inactivation system of kangaroos has been investigated in this study by using tritiated uridine-induced chromosome aberrations to distinguish the active from the inactive X. Previous work in eutherian mammals has demonstrated that constitutive heterochromatic chromosome regions are less susceptible to breakage by tritiated uri dine than euchromatic regions. The results of a comparison between the paternal X chromosome of a wallaroo x red kangaroo hybrid female and the two X chromosomes of a red kangaroo female suggested that the facultative heterochromatin of the X is also less susceptible to breakage by this treatment. However there were significantly more breaks of the paternal X in fibroblasts than in lymphocytes of the hybrid female, which agrees with biochemical findings suggesting activation of the paternal X in fibroblasts. Our results strengthen the suggestion of other workers that the reduced number of aberrations in heterochromatin occurs because such breaks occur principally when the DNA and labelled RNA are in apposition during transcription. Some evidence was found of an apparent toxicity effect of the tritiated uridine solution on the cells.

scholarly journals DNA metylation as one of the main mechanisms of gene activity regulation

2004 ◽  
Vol 2 (1) ◽  
pp. 27-37
Author(s):  
Anna A Pendina ◽  
Vera V Grinkevich ◽  
Tatyana V Kuznetsova ◽  
Vladislav S Baranov
Keyword(s):  
Dna Methylation ◽  
Genomic Imprinting ◽  
X Chromosome ◽  
Epigenetic Inheritance ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Gene Repression ◽  
Activity Regulation ◽  
Inherited Diseases

 DNA methylation is one of the main mechanisms of epigenetic inheritance in eukaryotes. In this review we looked through the ways of 5-methylcytosin origin, it's distribution in genome, the mechanism of gene repression via hypermetilation, the role of metylation in genomic imprinting and in X-chromosome inactivation, in embryogenesis of mammals, in the processes of oncogenesis and in etiology of some common human inherited diseases

scholarly journals Functional Analysis of the DXPas34Locus, a 3′ Regulator of Xist Expression

1999 ◽  
Vol 19 (12) ◽  
pp. 8513-8525 ◽  
Author(s):  
E. Debrand ◽  
C. Chureau ◽  
D. Arnaud ◽  
P. Avner ◽  
E. Heard
Keyword(s):  
X Chromosome ◽  
Yeast Artificial Chromosome ◽  
Es Cells ◽  
Artificial Chromosome ◽  
Antisense Transcription ◽  
Regulatory Elements ◽  
X Inactivation ◽  
X Chromosomes ◽  
Inactivation Center ◽  
Controlling Element

ABSTRACT X inactivation in female mammals is controlled by a key locus on the X chromosome, the X-inactivation center (Xic). The Xic controls the initiation and propagation of inactivation in cis. It also ensures that the correct number of X chromosomes undergo inactivation (counting) and determines which X chromosome becomes inactivated (choice). The Xist gene maps to the Xic region and is essential for the initiation of X inactivation in cis. Regulatory elements of X inactivation have been proposed to lie 3′ toXist. One such element, lying 15 kb downstream ofXist, is the DXPas34 locus, which was first identified as a result of its hypermethylation on the active X chromosome and the correlation of its methylation level with allelism at the X-controlling element (Xce), a locus known to affect choice. In this study, we have tested the potential function of theDXPas34 locus in Xist regulation and X-inactivation initiation by deleting it in the context of largeXist-containing yeast artificial chromosome transgenes. Deletion of DXPas34 eliminates both Xistexpression and antisense transcription present in this region in undifferentiated ES cells. It also leads to nonrandom inactivation of the deleted transgene upon differentiation. DXPas34 thus appears to be a critical regulator of Xist activity and X inactivation. The expression pattern of DXPas34 during early embryonic development, which we report here, further suggests that it could be implicated in the regulation of imprintedXist expression.

X Chromosome Inactivation and Imprinting

1996 ◽  
Vol 45 (1-2) ◽  
pp. 85-85
Author(s):  
M.F. Lyon
Keyword(s):  
X Chromosome ◽  
Germ Cells ◽  
Blastocyst Stage ◽  
X Inactivation ◽  
Xist Gene ◽  
Paternal Allele ◽  
Xist Expression ◽  
Cell Stage ◽  
Reading Frame ◽  
Genetic Imprinting

In contrast to the random inactivation of either maternal or paternal X-chromosome in the somatic cells of eutherian mammals, in marsupials the paternal X-chromosome is preferentially inactivated in all cells. Similar exclusively paternal X-inactivation occurs in two extraembryonic cell lineages of mice and rats. Thus, genetic imprinting is an important feature of X-inactivation. In embryonic development the initiation of X-inactivation is thought to occur through the X-inactivation centre, located on the X-Chromosome, and thus imprinting probably acts through this centre. A candidate gene for a role in the inactivation centre is Xist (X inactive specific transcript) which is expressed only from the inactive X-Chromosome. The expression of Xist in the mouse embryo is appropriate for it to be a cause rather than a consequence of inactivation. It appears before inactivation, and only the paternal allele is expressed in the extraembryonic lineages. In the germ cells also changes in X-chromosome activity are accompanied by changes in Xist expression. Studies of methylation of the Xist gene have shown that in male tissues where Xist is not active it is fully methylated, whereas in the female the allele on the active X-chromosome only is methylated. In male germ cells, where Xist is expressed, it is demethylated and the demethylation persists in mature spermatozoa. Thus a methylation difference in germ cells could possibly be the imprint. In androgenotes, with paternally derived chromosomes, Xist is expressed at the 4-cell stage, whereas in gynogenotes and parthenogenotes expression does not appear until the blastocyst stage. Thus, Xist expression shows imprinting. When expression appears in parthenogenotes it is random, suggesting that the imprint has been lost. The Xist gene has no open reading frame and is thought to act through mRNA but its function is unknown.

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