scholarly journals Progress in understanding the molecular mechanism of Xist RNA function through genetics

2017 ◽  
Vol 372 (1733) ◽  
pp. 20160368 ◽  
Author(s):  
Asun Monfort ◽  
Anton Wutz
Keyword(s):  
X Chromosome ◽  
Noncoding Rna ◽  
Recent Progress ◽  
Molecular Level ◽  
Mechanistic Model ◽  
Gene Repression ◽  
Inactive X Chromosome ◽  
Xist Rna ◽  
Biochemical Studies ◽  
Mary Lyon

The Xist gene produces a long noncoding RNA that initiates chromosome-wide gene repression on the inactive X chromosome in female mammals. Recent progress has advanced the understanding of Xist function at the molecular level. This review provides an overview of insights from genetic approaches and puts the new data in the context of an emerging mechanistic model as well as the existing literature. Some consideration is given on how independent biochemical studies on X inactivation help to advance on the wider question of chromatin regulation in the mammalian dosage compensation system. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.

scholarly journals Repeat E anchors Xist RNA to the inactive X chromosomal compartment through CDKN1A-interacting protein (CIZ1)

2017 ◽  
Vol 114 (40) ◽  
pp. 10654-10659 ◽  
Author(s):  
Hongjae Sunwoo ◽  
David Colognori ◽  
John E. Froberg ◽  
Yesu Jeon ◽  
Jeannie T. Lee
Keyword(s):  
X Chromosome ◽  
Single Molecule ◽  
Noncoding Rna ◽  
Zinc Finger Protein ◽  
Chromosome Territory ◽  
Interacting Protein ◽  
Single Molecule Level ◽  
Inactive X Chromosome ◽  
Xist Rna ◽  
Tight Association

X chromosome inactivation is an epigenetic dosage compensation mechanism in female mammals driven by the long noncoding RNA, Xist. Although recent genomic and proteomic approaches have provided a more global view of Xist’s function, how Xist RNA localizes to the inactive X chromosome (Xi) and spreads in cis remains unclear. Here, we report that the CDKN1-interacting zinc finger protein CIZ1 is critical for localization of Xist RNA to the Xi chromosome territory. Stochastic optical reconstruction microscopy (STORM) shows a tight association of CIZ1 with Xist RNA at the single-molecule level. CIZ1 interacts with a specific region within Xist exon 7–namely, the highly repetitive Repeat E motif. Using genetic analysis, we show that loss of CIZ1 or deletion of Repeat E in female cells phenocopies one another in causing Xist RNA to delocalize from the Xi and disperse into the nucleoplasm. Interestingly, this interaction is exquisitely sensitive to CIZ1 levels, as overexpression of CIZ1 likewise results in Xist delocalization. As a consequence, this delocalization is accompanied by a decrease in H3K27me3 on the Xi. Our data reveal that CIZ1 plays a major role in ensuring stable association of Xist RNA within the Xi territory.

scholarly journals BRCa1 participates in XIST RNa localization on inactive x chromosome

2019 ◽  
Vol 18 (2) ◽  
pp. 21-26
Author(s):  
E. A. Shestakova ◽  
T. A. Bogush
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Confocal Microscopy ◽  
X Chromosome ◽  
Fluorescent Microscopy ◽  
S Phase ◽  
Immunofluorescent Staining ◽  
Heterochromatin Protein ◽  
Inactive X Chromosome ◽  
Xist Rna

Introduction . Inactive X chromosome (Xi) is associated with noncoding XIST RNA, series of proteins and contains multiple epigenetic modifications that altogether determine a silence of the most of X-linked genes. Recently the data were obtained that tumor suppressor BRCA1 is also associated with Xi. The purpose of this study was to reveal the colocalization of BRCA1 and XIST RNA and precise spatial organization on Xi with the high resolution of confocal microscopy.Materials and methods . The object of the study is IMR90hTERT diploid immortalized fibroblast cell line. For BRCA1 and XIST RNA colocalization analysis on Xi the method of fluorescent hybridization in situ associated with immunofluorescent cell staining (immunoFISH) and confocal microscopy were used. For BRCA1 and heterochromatin protein-1 colocalization study the method of double immunofluorescent staining and common fluorescent microscopy were applied. Results . The study using confocal fluorescent microscopy with higher resolution has demonstrated at first the colocalization of BRCA1 with XIST RNA region of Xi revealed with XIST RNA probes and with replicating Xi and autosomes revealed with BrdU in late S-phase of cell cycle. Altogether, the data obtained suggest the involvement of BRCA1 in the inhibition of gene expression on Xi due to the regulation of XIST RNA association with Xi. Moreover, according to the results of confocal microscopy, BRCA1 also colocalizes with replicating Xi and autosomes revealed with BrdU in late S-phase of cell cycle. This indicates a possible involvement of this protein in the replication of pericentromeric repeats in cellular chromosomes. Colocalization of BRCA1 with heterochromatin protein-1α presented in pericentromeric regions of all chromosomes supports this suggestion.Conclusions . Altogether, the data obtained in this study suggest the involvement of BRCA1 in the inhibition of gene expression on Xi due to the association with noncoding inhibiting XIST RNA and in replication of heterochromatin regions. 

scholarly journals XIST RNA: a window into the broader role of RNA in nuclear chromosome architecture

2017 ◽  
Vol 372 (1733) ◽  
pp. 20160360 ◽  
Author(s):  
K. M. Creamer ◽  
J. B. Lawrence
Keyword(s):  
X Chromosome ◽  
Chromatin Condensation ◽  
Higher Order ◽  
Chromosome Architecture ◽  
Genome Wide ◽  
Xist Rna ◽  
Architectural Proteins ◽  
Mary Lyon ◽  
Attachment Factor

XIST RNA triggers the transformation of an active X chromosome into a condensed, inactive Barr body and therefore provides a unique window into transitions of higher-order chromosome architecture. Despite recent progress, how XIST RNA localizes and interacts with the X chromosome remains poorly understood. Genetic engineering of XIST into a trisomic autosome demonstrates remarkable capacity of XIST RNA to localize and comprehensively silence that autosome. Thus, XIST does not require X chromosome-specific sequences but operates on mechanisms available genome-wide. Prior results suggested XIST localization is controlled by attachment to the insoluble nuclear scaffold. Our recent work affirms that scaffold attachment factor A (SAF-A) is involved in anchoring XIST , but argues against the view that SAF-A provides a unimolecular bridge between RNA and the chromosome. Rather, we suggest that a complex meshwork of architectural proteins interact with XIST RNA. Parallel work studying the territory of actively transcribed chromosomes suggests that repeat-rich RNA ‘coats’ euchromatin and may impact chromosome architecture in a manner opposite of XIST . A model is discussed whereby RNA may not just recruit histone modifications, but more directly impact higher-order chromatin condensation via interaction with architectural proteins of the nucleus. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.

scholarly journals The search for the mouse X-chromosome inactivation centre

1990 ◽  
Vol 56 (2-3) ◽  
pp. 99-106 ◽  
Author(s):  
S. Rastan ◽  
S. D. M. Brown
Keyword(s):  
X Chromosome ◽  
Strong Evidence ◽  
Molecular Level ◽  
Molecular Genetic ◽  
X Chromosome Inactivation ◽  
X Inactivation ◽  
Chromosome Inactivation ◽  
Chromosome Identification ◽  
Female Embryo ◽  
Mary Lyon

SummaryThe phenomenon of X-chromosome inactivation in female mammals, whereby one of the two X chromosome present in each cell of the female embryo is inactivated early in development, was first described by Mary Lyon in 1961. Nearly 30 years later, the mechanism of X-chromosome inactivation remains unknown. Strong evidence has accumulated over the years, however, for the involvement of a major switch or inactivation centre on the mouse X chromosome. Identification of the inactivation centre at the molecular level would be an important step in understanding the mechanism of X-inactivation. In this paper we review the evidence for the existence and location of the X-inactivation centre on the mouse X-chromosome, present data on the molecular genetic mapping of this region, and describe ongoing strategies we are using to attempt to identify the inactivation centre at the molecular level.

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’.

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

2017 ◽  
Vol 372 (1733) ◽  
pp. 20160355 ◽  
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’.

scholarly journals The nuclear matrix protein CIZ1 facilitates localization of Xist RNA to the inactive X-chromosome territory

2017 ◽  
Vol 31 (9) ◽  
pp. 876-888 ◽  
Author(s):  
Rebeca Ridings-Figueroa ◽  
Emma R. Stewart ◽  
Tatyana B. Nesterova ◽  
Heather Coker ◽  
Greta Pintacuda ◽  
...  
Keyword(s):  
X Chromosome ◽  
Nuclear Matrix ◽  
Matrix Protein ◽  
Chromosome Territory ◽  
Nuclear Matrix Protein ◽  
Inactive X Chromosome ◽  
Xist Rna

scholarly journals Structural aspects of the inactive X chromosome

2017 ◽  
Vol 372 (1733) ◽  
pp. 20160357 ◽  
Author(s):  
Giancarlo Bonora ◽  
Christine M. Disteche
Keyword(s):  
X Chromosome ◽  
High Throughput Sequencing ◽  
Nuclear Periphery ◽  
Three Dimensional ◽  
Super Resolution ◽  
Structural Difference ◽  
X Inactivation ◽  
Striking Difference ◽  
Inactive X Chromosome ◽  
Mary Lyon

A striking difference between male and female nuclei was recognized early on by the presence of a condensed chromatin body only in female cells. Mary Lyon proposed that X inactivation or silencing of one X chromosome at random in females caused this structural difference. Subsequent studies have shown that the inactive X chromosome (Xi) does indeed have a very distinctive structure compared to its active counterpart and all autosomes in female mammals. In this review, we will recap the discovery of this fascinating biological phenomenon and seminal studies in the field. We will summarize imaging studies using traditional microscopy and super-resolution technology, which revealed uneven compaction of the Xi. We will then discuss recent findings based on high-throughput sequencing techniques, which uncovered the distinct three-dimensional bipartite configuration of the Xi and the role of specific long non-coding RNAs in eliciting and maintaining this structure. The relative position of specific genomic elements, including genes that escape X inactivation, repeat elements and chromatin features, will be reviewed. Finally, we will discuss the position of the Xi, either near the nuclear periphery or the nucleolus, and the elements implicated in this positioning. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.

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