Investigating X Chromosome Inactivation

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Investigating X Chromosome Inactivation

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Author : Sonja Pritchett
language : en
Publisher: LAP Lambert Academic Publishing
Release Date : 2011-01

Investigating X Chromosome Inactivation written by Sonja Pritchett and has been published by LAP Lambert Academic Publishing this book supported file pdf, txt, epub, kindle and other format this book has been release on 2011-01 with categories.

Females have two alleles for each gene on the X- chromosome, whereas males have only one. This inequality is balanced by X-chromosome inactivation (XCI). This process transcriptionally silences one X- chromosome in every female cell. The choice of which X-chromosome should be "turned-o " is considered to be random. Studies on mice have revealed that a locus on the X-chromosome, the X controlling element (Xce), signi cantly in uences the choice of which X- chromosome is inactivated. Renault et al. (2007) studied a family of which many of the females exhibit symptoms of the X-linked recessive disease, Haemophilia A. The XCI ratios of the women in this family were signi cantly di erent from what would be expected if the XCI process was random. This studies result is consistent with the human XCE hypothesis. Random and genetic models of XCI ratios are investigated here in theory and are compared to a sample of XCI ratios. Using goodness-of- fit testing, it is determined which models best fit the data. Anderson-Darling statistics and visual inspection of graphics suggest that a three allele genetic model is a good fit to the data, supporting the human XCE hypothesis.

Investigation Of X Chromosome Inactivation

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Author : Susan Carole Lester
language : en
Publisher:
Release Date : 1982

Investigation Of X Chromosome Inactivation written by Susan Carole Lester and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 1982 with Gene expression categories.

Investigating Random And Genetic Models For X Chromosome Inactivation

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Author : Sonja Merida Pritchett
language : en
Publisher:
Release Date : 2009

Investigating Random And Genetic Models For X Chromosome Inactivation written by Sonja Merida Pritchett and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2009 with X chromosome categories.

Investigation Of Cellular Mechanisms For Designating One Active And One Inactive X Chromosome In Female Mammals

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Author : Susanna Mlynarczyk-Evans
language : en
Publisher:
Release Date : 2006

Investigation Of Cellular Mechanisms For Designating One Active And One Inactive X Chromosome In Female Mammals written by Susanna Mlynarczyk-Evans and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2006 with categories.

In mammals, where females have two copies of the X chromosome and males have only one, X-chromosomal genes are expressed at comparable levels in both sexes. This dosage compensation is achieved by X-chromosome inactivation in females. At a critical decision point early in development, one of the two X chromosomes, apparently chosen at random in each cell, is transcriptionally silenced, and then clonally maintained for a female's lifetime. How can a cell distinguish between two chromosomes of the same DNA sequence to silence only one of them? What is the source of the apparent randomness? What restricts X-inactivation to females? In this thesis, I present research pertaining to these questions. Cytological investigations in pluripotent female cells revealed that, before X-inactivation is initiated, the future Xa and the future Xi already differ from one another along their entire lengths, suggesting they adopt distinct states. Analysis in cells poised for random X-inactivation supported a mechanism in which X chromosomes alternate between states in a mutually exclusive manner, such that the future Xi state is exhibited by the maternally-inherited X chromosome in 50% of cells and by the paternally-inherited X in the remaining 50%. Thus, upon initiation of X-inactivation, distinct properties of the future Xi may direct the silencing machinery to one chromosome per cell, leading to apparently random X-inactivation in the population. Analysis in pluripotent male cells showed that the single X chromosome does not adopt either state observed in females. The presence of a second copy of X-chromosomal sequences triggers adoption of two states, suggesting that the X-inactivation mechanism uses homology sensing to restrict the future Xi state to female cells. Taken together, this body of work reveals the parameters of the mechanism by which a mammalian cell differentiates one X chromosome for silencing in females, in a manner that appears random. Lessons from the X chromosomes may have implications for the regulation of random monoallelic genes on every autosome pair in the mammalian genome.

Investigating The Contribution Of The Non Coding Gene Ftx To X Chromosome Inactivation In Mammals

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Author : Giulia Furlan
language : en
Publisher:
Release Date : 2016

Investigating The Contribution Of The Non Coding Gene Ftx To X Chromosome Inactivation In Mammals written by Giulia Furlan and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2016 with categories.

X-chromosome inactivation (XCI) is a female-specific, chromosome-wide regulatory process that, in eutherians, ensures dosage compensation for X-linked genes between sexes. XCI is controlled by a cis-acting locus on the X-chromosome, the X-inactivation center (Xic), enriched in genes producing long non-coding RNAs (lncRNAs). The Xic-linked gene Xist is the master player of XCI, and produces a lncRNA that accumulates in cis on the X-chromosome and recruits the machinery responsible for initiation and propagation of silencing.The laboratory has identified an additional Xic-linked non-coding gene, Ftx. In this study, we could find that, in female Ftx-/- lines, XCI is strongly impaired, with a significant decrease in the levels of Xist expression and in the percentage of cells showing normal Xist accumulation patterns. Importantly, a high proportion of the cells that still retain Xist expression show abnormal X-chromosome coating and a decreased ability to silence X-linked genes. These data reveal that Ftx is a positive Xist regulator and it is required for proper XCI establishment. In female Ftx+/- lines, the levels of Xist expression and the percentage of cells showing normal Xist accumulation patterns are also decreased, albeit to a lower extent compared to Ftx-/- lines, suggesting that Ftx works in a copy-dependent manner. In addition, a high proportion of Ftx+/- cells display skewed X-inactivation, with preferential inactivation of the wild-type X chromosome. This suggests that Ftx role on Xist accumulation is mostly restricted in cis. Taken together, these results demonstrate that Ftx is required for XCI establishment, where it functions as a strong Xist activator.

Examining The Cause And Effect Of Skewed X Chromosome Inactivation Patterns In Humans

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Author : Nisa Karin Elaine Renault
language : en
Publisher:
Release Date : 2009

Examining The Cause And Effect Of Skewed X Chromosome Inactivation Patterns In Humans written by Nisa Karin Elaine Renault and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2009 with X chromosome categories.

Role Of Xist Ribonucleic Acid In The Maintenance Of X Chromosome Inactivation

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Author : Györgyi Csankovszki
language : en
Publisher:
Release Date : 2001

Role Of Xist Ribonucleic Acid In The Maintenance Of X Chromosome Inactivation written by Györgyi Csankovszki and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2001 with categories.

The role of Xist RNA in silencing the inactive X of female somatic cells was investigated by generating a conditional allele of the Xist gene. A system was set up in which reactivation of two X-linked genes, the endogenous Hprt gene and an X-linked GFP transgene, can be quantitatively assessed. Mouse embryonic fibroblasts derived from mice carrying the conditional Xist mutation were cultured and infected with an adenovirus vector carrying the gene for Cre recombinase. After Cre mediated deletion of Xist, the inactive X remained transcriptionally silent, late replicating, and hypoacetylated on histone H4, confirming that X-inactivation can be maintained in the absence of Xist RNA. However, the Xist mutant inactive X was no longer enriched in histone macroH2A 1. Furthermore, the reactivation rate of GFP and Hprt increased, indicating Xist RNA does contribute to gene repression on the inactive X. DNA methylation, histone hypoacetylation and Xist RNA were found to act synergistically in X chromosome silencing. To investigate whether Xist RNA can also silence the active X chromosome of male somatic cells, Xist expression on the active X was induced by demethylation. Demethylation was achieved by Cre mediated deletion of a conditional mutant allele of DNA methyltransferase-l (Dnmtl) in male fibroblasts. In these cells, Xist RNA coated the active X chromosome, in a pattern indistinguishable from coating of the inactive X of female cells. Although many Xist expressing chromosomes also transcribed X-linked genes Pgk-i and Hprt, in a small percent of cells Xist expression led to X chromosome inactivation. The proportion of chromosome expressing X-linked genes declined, and occasionally the X became late replicating, indicating that X-inactivation can be initiated in male somatic cells.

Females Are Mosaics

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Author : Barbara Migeon
language : en
Publisher: Oxford University Press
Release Date : 2007-03-15

Females Are Mosaics written by Barbara Migeon and has been published by Oxford University Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2007-03-15 with Medical categories.

Women can be described as genetic mosaics because they have two distinctly different types of cells throughout their bodies. Unlike males, who have one X chromosome (inherited from their mother), females have two X chromosomes in every cell (one from each parent). The fathers copy works in some cells, while the mothers copy works in others. These two X chromosomes often function differently, especially if one carries a defective gene. Much has been written about the Y chromosome and its role in inducing maleness. This will be the first book about the X chromosome as a key to female development and the role of X-related factors in the etiology of sex differences in human disease. Barbara Migeon, from the renowned McKusick-Nathan Institute at Johns Hopkins, is a major figure in clinical genetics and is eminently qualified to write this book, and she writes clearly and effectively. She describes both the underlying molecular mechanisms and the remarkable genetic consequences of X inactivation and its role in determining the biological concepts characteristic of women. Females are Mosaics will be valuable to geneticists, biologists, and all health professionals interested in women's health.

Investigating The Genome Wide Localization Of The Xist Lncrna And Its Roles In X Chromosome Dampening And The Formation Of The Inactive X Chromosome Compartment

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Author : Ying Xuan Shawn Tan
language : en
Publisher:
Release Date : 2021

Investigating The Genome Wide Localization Of The Xist Lncrna And Its Roles In X Chromosome Dampening And The Formation Of The Inactive X Chromosome Compartment written by Ying Xuan Shawn Tan and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2021 with categories.

Despite decades of biochemical, proteomic and genetic characterizations of the Xist longnon-coding RNA, the master regulator of X-chromosome inactivation (XCI), the spatiotemporal kinetics of Xist expression and how it coordinates the dynamic recruitment of protein effectors to direct robust gene silencing across the X-chromosome remain unexplored. Furthermore, most studies of Xist are conducted in the mouse system, so its role in mediating X-chromosome dampening (XCD), a unique mode of X-chromosome dosage compensation in humans, is still an open question. Therefore, in this thesis, I sought to plug this lack of understanding by (i) elucidating the molecular mechanism by which the chromosome-wide silencing compartment on the inactive X-chromosome (Xi) is formed and maintained across XCI, (ii) determining if XIST is responsible for XCD in human embryonic development, and (iii) characterizing the link between the genomewide localization patterns of Xist and its effect on gene silencing. iii In Chapter 2, we employed sophisticated super-resolution microscopy and single particle tracking techniques in living mouse embryonic stem cells (ESCs) undergoing XCI to precisely interrogate the spatiotemporal kinetics of Xist upregulation and its association with key protein partners that direct various aspects of XCI, and found that Xist first forms distinct foci that are locally restricted to about 50 sites across the Xi. Each site contains two Xist molecules, which seed the spatial concentration of integral protein interactors into what we term as a supra-molecular complex (SMC), made up of CIZ1 and CELF1 for localization of Xist across the Xi, PCGF5 and other components of Polycomb Repressive Complex 1 (PRC1) for inducing heterochromatinization and Xi compaction, and the transcriptional repressor SPEN, which is aided by its intrinsically disordered regions (IDRs) to promote phase separation-mediated aggregation of more SPEN molecules for the faithful and robust maintenance of X-linked gene silencing. In Chapter 3, we demonstrated the requirement of XIST in regulating XCD, as CRISPR-Cas9-mediated ablation of XIST in various human pluripotent stem cell (hPSC) lines that model XCD in vitro resulted in the loss of transcriptional downregulation on the dampened X-chromosome (Xd). By applying a high throughput genomics method that maps the chromatin binding of XIST, we discovered increased XIST enrichment on the Xi relative to the Xd, suggesting that XIST may be unable to exert complete silencing due to its reduced accumulation on the Xd. Moreover, we characterized a novel function of XIST, which can surprisingly propagate to certain autosomal regions beyond the X-chromosome territory, as well as repress some of the autosomal genes that it targets, resulting in a sex iv imbalance of the XIST-enriched autosomal gene expression levels that is also observed in human pre-implantation embryos in vivo. In Chapter 4, we built on our findings from Chapter 3 and showed that like in hPSCs in which the Xd exhibits a lower enrichment of XIST binding, early differentiating mouse ESCs also display diminished levels of Xist accumulation on the Xi, accompanied by reduced X-linked gene silencing, compared to the higher levels of Xist enrichment in late differentiated cells with complete XCI. Additionally, we characterized the distribution of Xist to autosomes in the mouse system, and illustrated how Xist spreading to the A- and B-compartments of the genome can be used to predict its differential ability to trigger gene silencing. Furthermore, we highlighted the remarkable ability of Xist to enact partial Xlinked gene repression in a mouse somatic cell line, which has surpassed the narrow developmental window surrounding pluripotency that was previously established in the XCI field for Xist-mediated silencing. Collectively, our findings gathered from these research projects have greatly expanded on the current knowledge about the molecular landscape established by Xist in setting up the Xi compartment, revealed insights on how XIST controls both XCI and XCD, and examined the genome-wide localization of Xist/XIST and its consequent gene silencing dynamics. In addition to addressing several open questions in the XCI field, our knowledge gained from this body of work on the Xist lncRNA may be extended to characterize other lncRNAs that contribute to the establishment and/or maintenance of gene regulatory nuclear compartments.

An Investigation Of Mammalian X Chromosome Inactivation Control Mechanisms

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Author : Graham John Young
language : en
Publisher:
Release Date : 1980

An Investigation Of Mammalian X Chromosome Inactivation Control Mechanisms written by Graham John Young and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 1980 with Cell hybridization categories.