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Edith Heard - One of the best experts on this subject based on the ideXlab platform.

  • the ftx noncoding locus controls x Chromosome Inactivation independently of its rna products
    Molecular Cell, 2018
    Co-Authors: Giulia Furlan, Edith Heard, Rafael Galupa, Nancy Gutierrez Hernandez, Christophe Huret, Joke Gerarda Van Bemmel, Antonio Romito, Celine Morey, Claire Rougeulle
    Abstract:

    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.

  • two coupled feedback loops explain random mono allelic xist upregulation at the onset of x Chromosome Inactivation
    bioRxiv, 2017
    Co-Authors: Verena Mutzel, Edith Heard, Ilona Dunkel, Ikuhiro Okamoto, Mitinori Saitou, Luca Giorgetti, Edda G. Schulz
    Abstract:

    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.

  • x Chromosome Inactivation new insights into cis and trans regulation
    Current Opinion in Genetics & Development, 2015
    Co-Authors: Rafael Galupa, Edith Heard
    Abstract:

    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.

  • noncoding rnas and epigenetic mechanisms during x Chromosome Inactivation
    Annual Review of Cell and Developmental Biology, 2014
    Co-Authors: Annevalerie Gendrel, Edith Heard
    Abstract:

    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.

  • x Chromosome Inactivation in development and cancer
    FEBS Letters, 2014
    Co-Authors: Ronan Chaligne, Edith Heard
    Abstract:

    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.

Anton Wutz - One of the best experts on this subject based on the ideXlab platform.

Huntington F. Willard - One of the best experts on this subject based on the ideXlab platform.

  • nonrandom x Chromosome Inactivation is influenced by multiple regions on the murine x Chromosome
    Genetics, 2012
    Co-Authors: Joanne L Thorvaldsen, Huntington F. Willard, Christopher Krapp, Marisa S Bartolomei
    Abstract:

    During the development of female mammals, one of the two X Chromosomes is inactivated, serving as a dosage-compensation mechanism to equalize the expression of X-linked genes in females and males. While the choice of which X Chromosome to inactivate is normally random, X Chromosome Inactivation can be skewed in F1 hybrid mice, as determined by alleles at the X Chromosome controlling element (Xce), a locus defined genetically by Cattanach over 40 years ago. Four Xce alleles have been defined in inbred mice in order of the tendency of the X Chromosome to remain active: Xcea < Xceb < Xcec < Xced. While the identity of the Xce locus remains unknown, previous efforts to map sequences responsible for the Xce effect in hybrid mice have localized the Xce to candidate regions that overlap the X Chromosome Inactivation center (Xic), which includes the Xist and Tsix genes. Here, we have intercrossed 129S1/SvImJ, which carries the Xcea allele, and Mus musculus castaneus EiJ, which carries the Xcec allele, to generate recombinant lines with single or double recombinant breakpoints near or within the Xce candidate region. In female progeny of 129S1/SvImJ females mated to recombinant males, we have measured the X Chromosome Inactivation ratio using allele-specific expression assays of genes on the X Chromosome. We have identified regions, both proximal and distal to Xist/Tsix, that contribute to the choice of which X Chromosome to inactivate, indicating that multiple elements on the X Chromosome contribute to the Xce.

  • x Chromosome Inactivation patterns of 1 005 phenotypically unaffected females
    American Journal of Human Genetics, 2006
    Co-Authors: James M Amoslandgraf, Huntington F. Willard, Amy Cottle, Robert M Plenge, Mike Friez, Charles E Schwartz, John W Longshore
    Abstract:

    X-Chromosome Inactivation is widely believed to be random in early female development and to result in a mosaic distribution of cells, approximately half with the paternally derived X Chromosome inactive and half with the maternally derived X Chromosome inactive. Significant departures from such a random pattern are hallmarks of a variety of clinical states, including being carriers for severe X-linked diseases or X-Chromosome cytogenetic abnormalities. To evaluate the significance of skewed patterns of X Inactivation, we examined patterns of X Inactivation in a population of >1,000 phenotypically unaffected females. The data demonstrate that only a very small proportion of unaffected females show significantly skewed Inactivation, especially during the neonatal period. By comparison with this data set, the degree of skewed Inactivation in a given individual can now be quantified and evaluated for its potential clinical significance.

  • skewed x Chromosome Inactivation is a common feature of x linked mental retardation disorders
    American Journal of Human Genetics, 2002
    Co-Authors: Robert M Plenge, Charles E Schwartz, Roger A Stevenson, Herbert A Lubs, Huntington F. Willard
    Abstract:

    Some deleterious X-linked mutations may result in a growth disadvantage for those cells in which the mutation, when on the active X Chromosome, affects cell proliferation or viability. To explore the relationship between skewed X-Chromosome Inactivation and X-linked mental retardation (XLMR) disorders, we used the androgen receptor X-Inactivation assay to determine X-Inactivation patterns in 155 female subjects from 24 families segregating 20 distinct XLMR disorders. Among XLMR carriers, ∼50% demonstrate markedly skewed X Inactivation (i.e., patterns ⩾80:20), compared with only ∼10% of female control subjects ( P

  • a promoter mutation in the xist gene in two unrelated families with skewed x Chromosome Inactivation
    Nature Genetics, 1997
    Co-Authors: Robert M Plenge, Charles E Schwartz, Anna K. Naumova, B D Hendrich, J F Arena, Carmen Sapienza, R M Winter, Huntington F. Willard
    Abstract:

    X-Chromosome Inactivation is the process by which a cell recognizes the presence of two copies of an X Chromosome early in the development of XX embryos and chooses one to be active and one to be inactive1. Although it is commonly believed that the initiation of X Inactivation is random, with an equal probability (50:50) that either X Chromosome will be the inactive X in a given cell, significant variation in the proportion of cells with either X inactive is observed both in mice heterozygous for alleles at the Xce locus2 and among normal human females in the population3–5. Families in which multiple females demonstrate extremely skewed Inactivation patterns that are otherwise quite rare in the general population are thought to reflect possible genetic influences on the X-Inactivation process5–7. Here we report a rare cytosine to guanine mutation in the XIST minimal promoter that underlies both epigenetic and functional differences between the two X Chromosomes in nine females from two unrelated families. All females demonstrate preferential Inactivation of the X Chromosome carrying the mutation, suggesting that there is an association between alterations in the regulation of XIST expression and X-Chromosome Inactivation.

  • Direct Detection of Non-Random X Chromosome Inactivation by Use of a Transcribed Polymorphism in the XIST Gene
    European Journal of Human Genetics, 1995
    Co-Authors: Jim L. Rupert, Carolyn J. Brown, Huntington F. Willard
    Abstract:

    As a result of X Chromosome Inactivation, females are mosaic for cell lineages in which either the paternal or the maternal X Chromosome is active, and, if Inactivation were random, each lineage should be present at approximately the same frequency. Detection of instances of non-random X Inactivation can be important both clinically and for the study of X Chromosome Inactivation. Identification of a single-base polymorphism in an expressed region of the human XIST gene has permitted the development of a direct PCR-based assay for randomness of X Inactivation. Oligonucleotide primers were designed, incorporating the variant base, and conditions established that allowed allele-specific PCR amplification. As the XIST gene is expressed only from the inactive X Chromosome, differential amplification of the alleles in cDNA from heterozygotes can be used as an indicator of non-random Inactivation. Using this assay, non-random X Chromosome Inactivation has been demonstrated in chromosomally abnormal cell lines and in lymphocytes from heterozygous, normal females. Virtually complete non-random X Inactivation was also shown in a mother and her daughter, suggesting the existence of some familial factor affecting X Chromosome Inactivation.

Joost Gribnau - One of the best experts on this subject based on the ideXlab platform.

  • rnf12 initiates x Chromosome Inactivation by targeting rex1 for degradation
    Nature, 2012
    Co-Authors: Cristina Gontan, Eskeatnaf Mulugeta Achame, Tahsin Stefan Barakat, Eveline Rentmeester, Jeroen Demmers, Wilfred F J Van Ijcken, Anton J Grootegoed, Joost Gribnau
    Abstract:

    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.

  • rnf12 activates xist and is essential for x Chromosome Inactivation
    PLOS Genetics, 2011
    Co-Authors: Tahsin Stefan Barakat, Eskeatnaf Mulugeta Achame, Eveline Rentmeester, Anton J Grootegoed, Nilhan Gunhanlar, Cristina Gontan Pardo, Mehrnaz Ghazvini, Ruben Boers, Annegien Kenter, Joost Gribnau
    Abstract:

    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.

  • rnf12 is an x encoded dose dependent activator of x Chromosome Inactivation
    Cell, 2009
    Co-Authors: Iris Jonkers, Eskeatnaf Mulugeta Achame, Tahsin Stefan Barakat, Eveline Rentmeester, Anton J Grootegoed, Annegien Kenter, Kim Monkhorst, Frank Grosveld, Joost Gribnau
    Abstract:

    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.

  • x Chromosome Inactivation is initiated in human preimplantation embryos
    American Journal of Human Genetics, 2009
    Co-Authors: Ilse M Van Den Berg, Joost Gribnau, Joop S E Laven, Mary Stevens, Iris Jonkers, Robertjan H Galjaard, Hikke J Van Doorninck
    Abstract:

    X Chromosome Inactivation (XCI) is the mammalian mechanism that compensates for the difference in gene dosage between XX females and XY males. Genetic and epigenetic regulatory mechanisms induce transcriptional silencing of one X Chromosome in female cells. In mouse embryos, XCI is initiated at the preimplantation stage following early whole-genome activation. It is widely thought that human embryos do not employ XCI prior to implantation. Here, we show that female preimplantation embryos have a progressive accumulation of XIST RNA on one of the two X Chromosomes, starting around the 8-cell stage. XIST RNA accumulates at the morula and blastocyst stages and is associated with transcriptional silencing of the XIST-coated chromosomal region. These findings indicate that XCI is initiated in female human preimplantation-stage embryos and suggest that preimplantation dosage compensation is evolutionarily conserved in placental mammals.

Nicolas Servant - One of the best experts on this subject based on the ideXlab platform.

  • line 1 activity in facultative heterochromatin formation during x Chromosome Inactivation
    Cell, 2010
    Co-Authors: Jennifer C Chow, Constance Ciaudo, Melissa Fazzari, Nathan Mise, Nicolas Servant
    Abstract:

    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

  • line 1 activity in facultative heterochromatin formation during x Chromosome Inactivation
    Cell, 2010
    Co-Authors: Jennifer C Chow, Constance Ciaudo, Melissa Fazzari, Nathan Mise, Nicolas Servant, Jacob L Glass, Matthew Attreed
    Abstract:

    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.