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Joost Gribnau - One of the best experts on this subject based on the ideXlab platform.
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reX1 is the critical target of rnf12 in imprinted X Chromosome Inactivation in mice
Nature Communications, 2018Co-Authors: Cristina Gontan, Tahsin Stefan Barakat, Eveline Rentmeester, Hegias Mirabontenbal, Aristea Magaraki, Catherine Dupont, Jeroen Demmers, Joost GribnauAbstract:In mice, imprinted X Chromosome Inactivation (iXCI) of the paternal X in the pre-implantation embryo and eXtraembryonic tissues is followed by X reactivation in the inner cell mass (ICM) of the blastocyst to facilitate initiation of random XCI (rXCI) in all embryonic tissues. RNF12 is an E3 ubiquitin ligase that plays a key role in XCI. RNF12 targets pluripotency protein REX1 for degradation to initiate rXCI in embryonic stem cells (ESCs) and loss of the maternal copy of Rnf12 leads to embryonic lethality due to iXCI failure. Here, we show that loss of ReX1 rescues the rXCI phenotype observed in Rnf12−/− ESCs, and that REX1 is the prime target of RNF12 in ESCs. Genetic ablation of ReX1 in Rnf12−/− mice rescues the Rnf12−/− iXCI phenotype, and results in viable and fertile Rnf12−/−:ReX1−/− female mice displaying normal iXCI and rXCI. Our results show that REX1 is the critical target of RNF12 in XCI.
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X Chromosome Inactivation in a female carrier of a 1 28 mb deletion encompassing the human X Inactivation centre
Philosophical Transactions of the Royal Society B, 2017Co-Authors: B De Hoon, Eveline Rentmeester, Joop S E Laven, Erik Splinter, B Eussen, J C W Douben, M Van De Heijning, J E M M De Klein, Jan Liebelt, Joost GribnauAbstract: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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rnf12 initiates X Chromosome Inactivation by targeting reX1 for degradation
Nature, 2012Co-Authors: Cristina Gontan, Eskeatnaf Mulugeta Achame, Tahsin Stefan Barakat, Eveline Rentmeester, Jeroen Demmers, Wilfred F J Van Ijcken, Anton J Grootegoed, Joost GribnauAbstract:The pluripotency factor REX1 is a key target of RNF12 during X-Chromosome Inactivation; degradation of REX1 by RNF12 leads to relief of its inhibitory action on X-Chromosome Inactivation. In placental mammals, X-linked gene dosage compensation between XY males and XX females is achieved by random Inactivation of one X Chromosome in female somatic cells. The E3 ubiquitin ligase RNF12 is required for initiation of X-Chromosome Inactivation (XCI) in embryonic stem cells, but its downstream targets have been unclear. Here, Gribnau and colleagues demonstrate that the pluripotency factor REX1 is a key target of RNF12 during XCI. RNF12 degradation of REX1 leads to relief of its inhibitory action on XCI. Evolution of the mammalian seX Chromosomes has resulted in a heterologous X and Y pair, where the Y Chromosome has lost most of its genes. Hence, there is a need for X-linked gene dosage compensation between XY males and XX females. In placental mammals, this is achieved by random Inactivation of one X Chromosome in all female somatic cells1. Upregulation of Xist transcription on the future inactive X Chromosome acts against TsiX antisense transcription, and spreading of Xist RNA in cis triggers epigenetic changes leading to X-Chromosome Inactivation. Previously, we have shown that the X-encoded E3 ubiquitin ligase RNF12 is upregulated in differentiating mouse embryonic stem cells and activates Xist transcription and X-Chromosome Inactivation2. Here we identify the pluripotency factor REX1 as a key target of RNF12 in the mechanism of X-Chromosome Inactivation. RNF12 causes ubiquitination and proteasomal degradation of REX1, and Rnf12 knockout embryonic stem cells show an increased level of REX1. Using chromatin immunoprecipitation sequencing, REX1 binding sites were detected in Xist and TsiX regulatory regions. OvereXpression of REX1 in female embryonic stem cells was found to inhibit Xist transcription and X-Chromosome Inactivation, whereas male ReX1+/− embryonic stem cells showed ectopic X-Chromosome Inactivation. From this, we propose that RNF12 causes REX1 breakdown through dose-dependent catalysis, thereby representing an important pathway to initiate X-Chromosome Inactivation. ReX1 and Xist are present only in placental mammals, which points to co-evolution of these two genes and X-Chromosome Inactivation.
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rnf12 activates Xist and is essential for X Chromosome Inactivation
PLOS Genetics, 2011Co-Authors: Tahsin Stefan Barakat, Eskeatnaf Mulugeta Achame, Eveline Rentmeester, Anton J Grootegoed, Nilhan Gunhanlar, Cristina Gontan Pardo, Mehrnaz Ghazvini, Ruben Boers, Annegien Kenter, Joost GribnauAbstract:In somatic cells of female placental mammals, one of the two X Chromosomes is transcriptionally silenced to accomplish an equal dose of X-encoded gene products in males and females. Initiation of random X Chromosome Inactivation (XCI) is thought to be regulated by X-encoded activators and autosomally encoded suppressors controlling Xist. Spreading of Xist RNA leads to silencing of the X Chromosome in cis. Here, we demonstrate that the dose dependent X-encoded XCI activator RNF12/RLIM acts in trans and activates Xist. We did not find evidence for RNF12-mediated regulation of XCI through TsiX or the Xist intron 1 region, which are both known to be involved in inhibition of Xist. In addition, we found that Xist intron 1, which contains a pluripotency factor binding site, is not required for suppression of Xist in undifferentiated ES cells. Analysis of female Rnf12−/− knockout ES cells showed that RNF12 is essential for initiation of XCI and is mainly involved in the regulation of Xist. We conclude that RNF12 is an indispensable factor in up-regulation of Xist transcription, thereby leading to initiation of random XCI.
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rnf12 is an X encoded dose dependent activator of X Chromosome Inactivation
Cell, 2009Co-Authors: Iris Jonkers, Eskeatnaf Mulugeta Achame, Tahsin Stefan Barakat, Eveline Rentmeester, Anton J Grootegoed, Annegien Kenter, Kim Monkhorst, Frank Grosveld, Joost GribnauAbstract:In somatic cells of female placental mammals, one X Chromosome is inactivated to minimize seX-related dosage differences of X-encoded genes. Random X Chromosome Inactivation (XCI) in the embryo is a stochastic process, in which each X has an independent probability to initiate XCI, triggered by the nuclear concentration of one or more X-encoded XCI-activators. Here, we identify the E3 ubiquitin ligase RNF12 as an important XCI-activator. Additional copies of mouse Rnf12 or human RNF12 result in initiation of XCI in male mouse ES cells and on both X Chromosomes in a substantial percentage of female mouse ES cells. This activity is dependent on an intact open reading frame of Rnf12 and correlates with the transgenic eXpression level of RNF12. Initiation of XCI is markedly reduced in differentiating female heterozygous Rnf12(+/-) ES cells. These findings provide evidence for a dose-dependent role of RNF12 in the XCI counting and initiation process.
Edith Heard - One of the best experts on this subject based on the ideXlab platform.
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the ftX noncoding locus controls X Chromosome Inactivation independently of its rna products
Molecular Cell, 2018Co-Authors: Giulia Furlan, Edith Heard, Rafael Galupa, Nancy Gutierrez Hernandez, Christophe Huret, Joke Gerarda Van Bemmel, Antonio Romito, Celine Morey, Claire RougeulleAbstract:Summary Accumulation of the Xist long noncoding RNA (lncRNA) on one X Chromosome is the trigger for X Chromosome Inactivation (XCI) in female mammals. Xist eXpression, which needs to be tightly controlled, involves a cis -acting region, the X-Inactivation center ( Xic ), containing many lncRNA genes that evolved concomitantly to Xist from protein-coding ancestors through pseudogeneization and loss of coding potential. Here, we uncover an essential role for the Xic -linked noncoding gene FtX in the regulation of Xist eXpression. We show that FtX is required in cis to promote Xist transcriptional activation and establishment of XCI. Importantly, we demonstrate that this function depends on FtX transcription and not on the RNA products. Our findings illustrate the multiplicity of layers operating in the establishment of XCI and highlight the diversity in the modus operandi of the noncoding players.
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two coupled feedback loops eXplain random mono allelic Xist upregulation at the onset of X Chromosome Inactivation
bioRxiv, 2017Co-Authors: Verena Mutzel, Edith Heard, Ilona Dunkel, Ikuhiro Okamoto, Mitinori Saitou, Luca Giorgetti, Edda G. SchulzAbstract:In female mammals, dosage compensation for X-linked genes is ensured through random X-Chromosome Inactivation, which is initiated by mono-allelic up-regulation of Xist. We use mathematical modeling to identify the regulatory principles required to establish the mono-allelic and female-specific Xist eXpression pattern and test model predictions eXperimentally. A cis-acting positive feedback, which in mice is mediated by mutual repression of Xist and its antisense transcript TsiX, together with a trans-acting negative feedback are sufficient to eXplain mono-allelic Xist up-regulation. The model can reproduce data from several mutant, aneuploid and polyploid murine cell lines and eXplains Xist eXpression patterns in other mammalian species. Furthermore, it predicts that transient, reversible bi-allelic Xist eXpression is not restricted to rabbits and humans but can also occur in mice, which we indeed confirm to occur in mouse embryos. Overall, our study provides a conceptual framework of the molecular mechanisms required to initiate random X-Chromosome Inactivation.
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X Chromosome Inactivation new insights into cis and trans regulation
Current Opinion in Genetics & Development, 2015Co-Authors: Rafael Galupa, Edith HeardAbstract:X-Chromosome Inactivation (XCI) is a developmentally associated process that evolved in mammals to enable gene dosage compensation between XX and XY individuals. In placental mammals, it is triggered by the long noncoding RNA Xist, which is produced from a compleX regulatory locus, the X-Inactivation centre (Xic). Recent insights into the regulatory landscape of the Xic, including its partitioning into topological associating domains (TADs) and its genetic dissection, have important implications for the monoallelic regulation of Xist. Here, we present some of the latest studies on X Inactivation with a special focus on the regulation of Xist, its various functions and the putative role of Chromosome conformation in regulating the dynamics of this locus during development and differentiation.
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noncoding rnas and epigenetic mechanisms during X Chromosome Inactivation
Annual Review of Cell and Developmental Biology, 2014Co-Authors: Annevalerie Gendrel, Edith HeardAbstract:In mammals, the process of X-Chromosome Inactivation ensures equivalent levels of X-linked gene eXpression between males and females through the silencing of one of the two X Chromosomes in female cells. The process is established early in development and is initiated by a unique locus, which produces a long noncoding RNA, Xist. The Xist transcript triggers gene silencing in cis by coating the future inactive X Chromosome. It also induces a cascade of chromatin changes, including posttranslational histone modifications and DNA methylation, and leads to the stable repression of all X-linked genes throughout development and adult life. We review here recent progress in our understanding of the molecular mechanisms involved in the initiation of Xist eXpression, the propagation of the Xist RNA along the Chromosome, and the cis-elements and trans-acting factors involved in the maintenance of the repressed state. We also describe the diverse strategies used by nonplacental mammals for X-Chromosome dosage compensation and highlight the common features and differences between eutherians and metatherians, in particular regarding the involvement of long noncoding RNAs.
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X Chromosome Inactivation in development and cancer
FEBS Letters, 2014Co-Authors: Ronan Chaligne, Edith HeardAbstract:X-Chromosome Inactivation represents an epigenetics paradigm and a powerful model system of facultative heterochromatin formation triggered by a non-coding RNA, Xist, during development. Once established, the inactive state of the Xi is highly stable in somatic cells, thanks to a combination of chromatin associated proteins, DNA methylation and nuclear organization. However, sporadic reactivation of X-linked genes has been reported during ageing and in transformed cells and disappearance of the Barr body is frequently observed in cancer cells. In this review we summarise current knowledge on the epigenetic changes that accompany X Inactivation and discuss the eXtent to which the inactive X Chromosome may be epigenetically or genetically perturbed in breast cancer.
Jeannie T Lee - One of the best experts on this subject based on the ideXlab platform.
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genetic intersection of tsiX and hedgehog signaling during the initiation of X Chromosome Inactivation
Developmental Cell, 2017Co-Authors: Brian C Del Rosario, Amanda M Del Rosario, Anthony Anselmo, Peggy I Wang, Ruslan I Sadreyev, Jeannie T LeeAbstract:Summary X-Chromosome Inactivation (XCI) silences one X Chromosome in the female mammal and is essential to peri-implantation development. XCI is thought to be cell autonomous, with all factors required being produced within each cell. Nevertheless, eXternal cues may eXist. Here, we search for such developmental signals by combining bioinformatic, biochemical, and genetic approaches. Using eX vivo and in vivo models, we identify the Hedgehog (HH) paracrine system as a candidate signaling cascade. HH signaling keeps XCI in check in pluripotent cells and is transduced by GLI transcription factors to binding sites in TsiX , the antisense repressor of XCI. GLI potentiates TsiX eXpression and impedes XCI. In vivo , mutating Indian Hedgehog results in a seX ratio bias against females, and the female lethality is rescued by a second-site mutation in TsiX . These data demonstrate a genetic and functional intersection between HH and XCI and support a role for intercellular signaling during XCI.
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X Chromosome Inactivation and epigenetic responses to cellular reprogramming
Annual Review of Genomics and Human Genetics, 2013Co-Authors: Derek Lessing, Montserrat C Anguera, Jeannie T LeeAbstract:Reprogramming somatic cells to derive induced pluripotent stem cells (iPSCs) has provided a new method to model disease and holds great promise for regenerative medicine. Although genetically identical to their donor somatic cells, iPSCs undergo substantial changes in the epigenetic landscape during reprogramming. One such epigenetic process, X Chromosome Inactivation (XCI), has recently been shown to vary widely in human female iPSCs and embryonic stem cells (ESCs). XCI is a form of dosage compensation whose chief regulator is the noncoding RNA Xist. In mouse iPSCs and ESCs, Xist eXpression and XCI strictly correlate with the pluripotent state, but no such correlation eXists in humans. Lack of XIST eXpression in human cells is linked to reduced developmental potential and an altered transcriptional profile, including upregulation of genes associated with cancer, which has therefore led to concerns about the safety of pluripotent stem cells for use in regenerative medicine. In this review, we describe how different states of XIST eXpression define three classes of female human pluripotent stem cells and eXplore progress in discovering the reasons for these variations and how they might be countered.
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new and Xisting regulatory mechanisms of X Chromosome Inactivation
Current Opinion in Genetics & Development, 2012Co-Authors: Yesu Jeon, Kavitha Sarma, Jeannie T LeeAbstract:Equalization of X linked gene eXpression is necessary in mammalian cells due to the presence of two X Chromosomes in females and one in males. To achieve this, all female cells inactivate one of the two X Chromosomes during development. This process, termed X Chromosome Inactivation (XCI), is a quintessential epigenetic phenomenon and involves a compleX interplay between noncoding RNAs and protein factors. Progress in this area of study has consequently resulted in new approaches to study epigenetics and regulatory RNA function. Here we will discuss recent developments in the field that have advanced our understanding of XCI and its regulatory mechanisms.
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gracefully ageing at 50 X Chromosome Inactivation becomes a paradigm for rna and chromatin control
Nature Reviews Molecular Cell Biology, 2011Co-Authors: Jeannie T LeeAbstract:The discovery of X-Chromosome Inactivation (XCI) celebrated its golden anniversary this year. Originally offered as an eXplanation for the establishment of genetic equality between males and females, 50 years on, XCI presents more than a curious gender-based phenomenon that causes silencing of seX Chromosomes. How have the mysteries of XCI unfolded? And what general lessons can be eXtracted? Several of the cell biological mechanisms that are used to establish the inactive X Chromosome, including regulatory networks of non-coding RNAs and unusual nuclear dynamics, are now suspected to hold true for processes occurring on a genome-wide scale.
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the long noncoding rna jpX is a molecular switch for X Chromosome Inactivation
Cell, 2010Co-Authors: Di Tian, Jeannie T Lee, Sha SunAbstract:Once protein-coding, the X-Inactivation center (Xic) is now dominated by large noncoding RNAs (ncRNA). X Chromosome Inactivation (XCI) equalizes gene eXpression between mammalian males and females by inactivating one X in female cells. XCI requires Xist, an ncRNA that coats the X and recruits Polycomb proteins. How Xist is controlled remains unclear but likely involves negative and positive regulators. For the active X, the antisense TsiX RNA is an established Xist repressor. For the inactive X, here, we identify Xic-encoded JpX as an Xist activator. JpX is developmentally regulated and accumulates during XCI. Deleting JpX blocks XCI and is female lethal. Posttranscriptional JpX knockdown recapitulates the knockout, and supplying JpX in trans rescues lethality. Thus, JpX is trans-acting and functions as ncRNA. Furthermore, ΔJpX is rescued by truncating TsiX, indicating an antagonistic relationship between the ncRNAs. We conclude that Xist is controlled by two RNA-based switches: TsiX for Xa and JpX for Xi.
Nicolas Servant - One of the best experts on this subject based on the ideXlab platform.
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line 1 activity in facultative heterochromatin formation during X Chromosome Inactivation
Cell, 2010Co-Authors: Jennifer C Chow, Constance Ciaudo, Melissa Fazzari, Nathan Mise, Nicolas ServantAbstract:Summary During X Chromosome Inactivation (XCI), Xist RNA coats and silences one of the two X Chromosomes in female cells. Little is known about how XCI spreads across the Chromosome, although LINE-1 elements have been proposed to play a role. Here we show that LINEs participate in creating a silent nuclear compartment into which genes become recruited. A subset of young LINE-1 elements, however, is eXpressed during XCI, rather than being silenced. We demonstrate that such LINE eXpression requires the specific heterochromatic state induced by Xist. These LINEs often lie within escape-prone regions of the X Chromosome, but close to genes that are subject to XCI, and are associated with putative endo-siRNAs. LINEs may thus facilitate XCI at different levels, with silent LINEs participating in assembly of a heterochromatic nuclear compartment induced by Xist, and active LINEs participating in local propagation of XCI into regions that would otherwise be prone to escape. PaperClip
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line 1 activity in facultative heterochromatin formation during X Chromosome Inactivation
Cell, 2010Co-Authors: Jennifer C Chow, Constance Ciaudo, Melissa Fazzari, Nathan Mise, Nicolas Servant, Jacob L Glass, Matthew AttreedAbstract:During X Chromosome Inactivation (XCI), Xist RNA coats and silences one of the two X Chromosomes in female cells. Little is known about how XCI spreads across the Chromosome, although LINE-1 elements have been proposed to play a role. Here we show that LINEs participate in creating a silent nuclear compartment into which genes become recruited. A subset of young LINE-1 elements, however, is eXpressed during XCI, rather than being silenced. We demonstrate that such LINE eXpression requires the specific heterochromatic state induced by Xist. These LINEs often lie within escape-prone regions of the X Chromosome, but close to genes that are subject to XCI, and are associated with putative endo-siRNAs. LINEs may thus facilitate XCI at different levels, with silent LINEs participating in assembly of a heterochromatic nuclear compartment induced by Xist, and active LINEs participating in local propagation of XCI into regions that would otherwise be prone to escape.
Anton Wutz - One of the best experts on this subject based on the ideXlab platform.
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gene silencing in X Chromosome Inactivation advances in understanding facultative heterochromatin formation
Nature Reviews Genetics, 2011Co-Authors: Anton WutzAbstract:Mammalian X-Chromosome Inactivation is a paradigm for understanding gene silencing by heterochromatin formation. This Review discusses recent progress and outstanding questions surrounding the initiation and maintenance of X-Chromosome Inactivation and its reactivation during both normal development and artificial reprogramming.
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gene silencing in X Chromosome Inactivation advances in understanding facultative heterochromatin formation
Nature Reviews Genetics, 2011Co-Authors: Anton WutzAbstract:In female mammals, one of the two X Chromosomes is silenced for dosage compensation between the seXes. X-Chromosome Inactivation is initiated in early embryogenesis by the Xist RNA that localizes to the inactive X Chromosome. During development, the inactive X Chromosome is further modified, a specialized form of facultative heterochromatin is formed and gene repression becomes stable and independent of Xist in somatic cells. The recent identification of several factors involved in this process has provided insights into the mechanism of Xist localization and gene silencing. The emerging picture is compleX and suggests that Chromosome-wide silencing can be partitioned into several steps, the molecular components of which are starting to be defined.
