scholarly journals Advances in understanding chromosome silencing by the long non-coding RNA Xist

2013 ◽  
Vol 368 (1609) ◽  
pp. 20110325 ◽  
Author(s):  
Takashi Sado ◽  
Neil Brockdorff
Keyword(s):  
X Chromosome ◽  
Classical Model ◽  
X Inactivation ◽  
X Chromosomes ◽  
Current State ◽  
Non Coding Rna ◽  
Xist Rna ◽  
To Come ◽  
In Cis ◽  
Long Non Coding Rna

In female mammals, one of the two X chromosomes becomes genetically silenced to compensate for dosage imbalance of X-linked genes between XX females and XY males. X chromosome inactivation (X-inactivation) is a classical model for epigenetic gene regulation in mammals and has been studied for half a century. In the last two decades, efforts have been focused on the X inactive-specific transcript ( Xist ) locus, discovered to be the master regulator of X-inactivation. The Xist gene produces a non-coding RNA that functions as the primary switch for X-inactivation, coating the X chromosome from which it is transcribed in cis . Significant progress has been made towards understanding how Xist is regulated at the onset of X-inactivation, but our understanding of the molecular basis of silencing mediated by Xist RNA has progressed more slowly. A picture has, however, begun to emerge, and new tools and resources hold out the promise of further advances to come. Here, we provide an overview of the current state of our knowledge, what is known about Xist RNA and how it may trigger chromosome silencing.

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.

scholarly journals A RIF1 and KAP1-based, double-bookmarking system generates a toggle switch that stabilises the identities of the active and inactive X chromosomes during random X inactivation in mouse

2020 ◽  
Author(s):  
Elin Enervald ◽  
Rossana Foti ◽  
Lynn Marie Powell ◽  
Agnieszka Piszczek ◽  
Sara C.B. Buonomo
Keyword(s):  
X Chromosome ◽  
Embryonic Stem ◽  
X Inactivation ◽  
Allelic Association ◽  
Toggle Switch ◽  
X Chromosomes ◽  
Non Coding Rna ◽  
The Future ◽  
Long Non Coding Rna ◽  
Stochastic Event

ABSTRACTDosage compensation for the X chromosome-linked genes in female placental mammals is achieved through the random silencing of one of the two X chromosomes. The onset of random X inactivation in mouse embryos and in differentiating embryonic stem cells requires the switch from a symmetric state, where both X chromosomes are equivalent, to an asymmetric state, where the identity of the future inactive and active X chromosomes are assigned. This “choice”, initiated by a stochastic event, needs to evolve into a stable and transmissible state. The transition from bi- to mono-allelic expression of the long non-coding RNA Tsix is thought to be one of the initial events breaking the symmetry of the two X chromosomes. Here we show that the asymmetric expression of Tsix triggers in turn the switch of RIF1 association with the Xist promoter from dynamic and symmetric to stable and asymmetric (on the future inactive X). On the future inactive X, RIF1 then plays an essential role in the upregulation of Xist, thus initiating the consolidation and stable transmission of the identity of the inactive X. Tsix-dependent exclusion of RIF1 from the future active X chromosome in turn permits the association of KAP1 with the Xist promoter, thus marking the future active X chromosome. Timely mono-allelic association of KAP1 is important for a stable choice and for X inactivation. We present here a double-bookmarking system, based on the mutually exclusive relationships of Tsix and RIF1, and RIF1 and KAP1. This system coordinates the identification of the active and inactive X chromosomes and initiates a self-sustaining loop that transforms an initially stochastic event into a stably inherited asymmetric X chromosome state.

scholarly journals Stabilization and Localization of Xist RNA are Controlled by Separate Mechanisms and are Not Sufficient for X Inactivation

1998 ◽  
Vol 142 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Christine Moulton Clemson ◽  
Jennifer C. Chow ◽  
Carolyn J. Brown ◽  
Jeanne Bentley Lawrence
Keyword(s):  
X Chromosome ◽  
Somatic Cells ◽  
X Inactivation ◽  
X Chromosomes ◽  
Xist Rna ◽  
Chromosomal Association ◽  
Specific Factors ◽  
Species Specific ◽  
Rna Accumulation ◽  
First Time

These studies address whether XIST RNA is properly localized to the X chromosome in somatic cells where human XIST expression is reactivated, but fails to result in X inactivation (Tinker, A.V., and C.J. Brown. 1998. Nucl. Acids Res. 26:2935–2940). Despite a nuclear RNA accumulation of normal abundance and stability, XIST RNA does not localize in reactivants or in naturally inactive human X chromosomes in mouse/ human hybrid cells. The XIST transcripts are fully stabilized despite their inability to localize, and hence XIST RNA localization can be uncoupled from stabilization, indicating that these are separate steps controlled by distinct mechanisms. Mouse Xist RNA tightly localized to an active X chromosome, demonstrating for the first time that the active X chromosome in somatic cells is competent to associate with Xist RNA. These results imply that species-specific factors, present even in mature, somatic cells that do not normally express Xist, are necessary for localization. When Xist RNA is properly localized to an active mouse X chromosome, X inactivation does not result. Therefore, there is not a strict correlation between Xist localization and chromatin inactivation. Moreover, expression, stabilization, and localization of Xist RNA are not sufficient for X inactivation. We hypothesize that chromosomal association of XIST RNA may initiate subsequent developmental events required to enact transcriptional silencing.

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 A role for YY1 in sex-biased transcription revealed through X-linked promoter activity and allelic binding analyses

2016 ◽  
Author(s):  
Chih-yu Chen ◽  
Wenqiang Shi ◽  
Allison M. Matthews ◽  
Yifeng Li ◽  
David J. Arenillas ◽  
...  
Keyword(s):  
X Chromosome ◽  
Specific Binding ◽  
Positive Association ◽  
Binding Motif ◽  
Transcription Start ◽  
Transcription Factor Binding Motif ◽  
Transcription Start Sites ◽  
Non Coding Rna ◽  
Allelic Gene ◽  
Long Non Coding Rna

AbstractSex differences in susceptibility and progression have been reported in numerous diseases. Female cells have two copies of the X chromosome with X-chromosome inactivation imparting mono-allelic gene silencing for dosage compensation. However, a subset of genes, named escapees, escape silencing and are transcribed bi-allelically resulting in sexual dimorphism. Here we conducted analyses of the sexes using human datasets to gain perspectives in such regulation. We identified transcription start sites of escapees (escTSSs) based on higher transcription levels in female cells using FANTOM5 CAGE data. Significant over-representations of YY1 transcription factor binding motif and ChIP-seq peaks around escTSSs highlighted its positive association with escapees. Furthermore, YY1 occupancy is significantly biased towards the inactive X (Xi) at long non-coding RNA loci that are frequent contacts of Xi-specific superloops. Our study elucidated the importance of YY1 on transcriptional activity on Xi in general through sequence-specific binding, and its involvement at superloop anchors.

X-chromosome inactivation in XX androgenetic mouse embryos surviving implantation

Development ◽  
2000 ◽  
Vol 127 (19) ◽  
pp. 4137-4145 ◽  
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.

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.

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

scholarly journals What makes the maternal X chromosome resistant to undergoing imprinted X inactivation?

2017 ◽  
Vol 372 (1733) ◽  
pp. 20160365 ◽  
Author(s):  
Takashi Sado
Keyword(s):  
X Chromosome ◽  
Chromatin Structure ◽  
Noncoding Rna ◽  
X Inactivation ◽  
Preimplantation Embryos ◽  
Parental Origin ◽  
Random Fashion ◽  
In Cis ◽  
Mary Lyon ◽  
Extraembryonic Tissues

In the mouse, while either X chromosome is chosen for inactivation in a random fashion in the embryonic tissue, the paternally derived X chromosome is preferentially inactivated in the extraembryonic tissues. It has been shown that the maternal X chromosome is imprinted so as not to undergo inactivation in the extraembryonic tissues. X-linked noncoding Xist RNA becomes upregulated on the X chromosome that is to be inactivated. An antisense noncoding RNA, Tsix , which occurs at the Xist locus and has been shown to negatively regulate Xist expression in cis, is imprinted to be expressed from the maternal X in the extraembryonic tissues. Although Tsix appears to be responsible for the imprint laid on the maternal X, those who disagree with this idea would point out the fact that Tsix has not yet been expressed from the maternal X when Xist becomes upregulated on the paternal but not the maternal X at the onset of imprinted X-inactivation in preimplantation embryos. Recent studies have demonstrated, however, that there is a prominent difference in the chromatin structure at the Xist locus depending on the parental origin, which I suggest might account for the repression of maternal Xist in the absence of maternal Tsix at the preimplantation stages. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.

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.

Sign in / Sign up

Export Citation Format

Share Document