Dissertations / Theses on the topic 'X-chromosome inactivation'
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Norris, Dominic Paul. "X chromosome inactivation in the mouse." Thesis, Open University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282142.
Full textBenjamin, Don. "Molecular studies of human X chromosome inactivation." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318784.
Full textPaterno, Gary David. "X chromosome inactivation in mouse embryonal carcinoma cells." Thesis, University of Ottawa (Canada), 1985. http://hdl.handle.net/10393/4629.
Full textMetello, de Napoles Mariana. "Epigenetic modifications during X-chromosome inactivation and reactivation." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.422058.
Full textAger, Miranda. "Mechanisms of X chromosome inactivation : a transgenic approach." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342240.
Full text林德深 and Tak-sum Lam. "A biochemical study of mammalian x chromosome inactivation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1987. http://hub.hku.hk/bib/B31981306.
Full textDossin, François. "Mechanistic dissection of SPEN functionduring X chromosome inactivation." Thesis, Université Paris sciences et lettres, 2021. http://www.theses.fr/2021UPSLS042.
Full textIn female placental mammals, dosage compensation of X-linked gene expression is achieved early during development through transcriptional inactivation of one of the two X chromosomes (XCI). This process is dependent on Xist, a long non-coding RNA which coats and silences the X chromosome from which it is transcribed. The mechanisms through which Xist initiates transcriptional silencing during XCI remain however completely unknown. In 2015, several studies identified that the SPEN protein binds Xist RNA directly, and its implication in mediating gene silencing was reported. However, its precise function and mechanism(s) of action during XCI are unclear.During my PhD, I made use of a conditional loss of function approach, the auxin inducible degron, to acutely deplete SPEN in mouse embryonic stem cells (mESCs) undergoing XCI. Using this approach, I demonstrate that SPEN is absolutely necessary for chromosome-wide Xist-mediated gene silencing during initiation of XCI. Furthermore, using conditional Spen KO mouse embryos, I show that SPEN is also required for the transcriptional inactivation of the paternal X chromosome during imprinted X inactivation. Depleting SPEN in differentiated cells, in which XCI has been established, reveals that SPEN is neither required to maintain gene silencing nor to preserve the spatial organization of the inactive X chromosome.By combining fixed and live cell imaging of Xist and SPEN, I show that SPEN colocalizes with Xist RNA, and accumulates on the X chromosome, immediately upon Xist upregulation, suggesting that SPEN can initiate gene silencing very early on during XCI. Profiling SPEN chromatin binding sites reveals that SPEN is recruited to promoters and enhancers of active genes specifically. The magnitude of SPEN recruitment to X-linked promoters dictates the efficiency with which these genes will be silenced. Remarkably, SPEN disengages from chromatin after gene silencing, indicating that active transcription required for SPEN’s association with chromatin.Using a functional complementation approach, I identify the SPOC domain as the effector of SPEN’s gene silencing activity during XCI. Artificial tethering of SPOC to Xist RNA results in transcriptional repression along the entire X chromosome, demonstrating that SPOC contains all the sufficient potential to instruct gene silencing during XCI. I further characterize the protein interactors of SPOC using mass spectrometry and reveal that SPOC interacts with several protein complexes involved in repressing transcription, including the NCoR/SMRT (histone deacetylation), the NuRD (nucleosome remodeling/histone deacetylation) and the m6A writing (governing mRNA fate) complexes. Finally, several transcription initiation and elongation factors are found to interact with SPOC, as well as the RNA polymerase II (RNAPII) transcription machinery.I identify that SPOC interacts directly and specifically with the C-terminal domain (CTD) of RNAPII only when the latter is phosphorylated on Ser5, and determine the 3D structure of the SPOC/RNAPII-CTD Ser5-P complex at 1.8Å resolution. These results suggest that SPEN could directly repress transcription during XCI by interfering with RNAPII-CTD Ser5-P templated processes.Altogether, my PhD work reveals that SPEN is essential for chromosome-wide transcriptional silencing during XCI, both in mESCs and in vivo. Following Xist upregulation, SPEN is immediately recruited to active gene promoters and enhancers, silences transcription, and subsequently disengages from chromatin. Through its RRMs and SPOC domains, SPEN acts as a molecular integrator, bridging Xist with histone deacetylases, nucleosome remodelers, RNA methyltransferases and most importantly, the transcription machinery
Lam, Tak-sum. "A biochemical study of mammalian x chromosome inactivation." [Hong Kong : University of Hong Kong], 1987. http://sunzi.lib.hku.hk/hkuto/record.jsp?B12827186.
Full textForrester, Lesley Margaret. "Murine haematopoiesis : studies using X chromosome-inactivation mosaics." Thesis, University of Edinburgh, 1987. http://hdl.handle.net/1842/28042.
Full textSprong, Amy Nicole. "X Chromosome Aneuploidy: A Look at the Effects of X Inactivation." Miami University Honors Theses / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=muhonors1209079846.
Full textCotton, Allison Marie. "Patterns of DNA methylation on the human X chromosome and use in analyzing X-chromosome inactivation." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/40363.
Full textAdra, Chaker Nadim. "X chromosome inactivation and the phosphoglycerate kinase gene family." Thesis, University of Ottawa (Canada), 1988. http://hdl.handle.net/10393/5308.
Full textSharp, Andrew James. "A molecular study of X chromosome inactivation in humans." Thesis, University of Southampton, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252456.
Full textSpotswood, Hugh Timothy. "Histone modification and the epigenetics of X chromosome inactivation." Thesis, University of Birmingham, 2003. http://etheses.bham.ac.uk//id/eprint/230/.
Full textApedaile, Anwyn Emily. "Dynamics of DNA methylation on the mammalian X-chromosome during X-inactivation." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444592.
Full textLuikenhuis, Sandra 1972. "Studies on X chromosome inactivation and the X-linked disease Rett syndrome." Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/28676.
Full textIncludes bibliographical references.
(cont.) the RTT phenotype.
Deletion of the Xist gene results in skewed X-inactivation. To distinguish primary non-random choice from post-choice selection, we analyzed X-inactivation in early embryonic development in the presence of two different Xist deletions. We found that Xist is an important choice element, and that in the absence of an intact Xist gene, the X chromosome will never be chosen as the active X. To understand the molecular mechanisms that affect choice we analyzed the role of replication timing prior to X-inactivation. The X chromosomes replicated asynchronously before X-inactivation but analysis of cell-lines with skewed X-inactivation showed no preference for one of the two Xist alleles to replicate early, indicating that asynchronous replication timing prior to X-inactivation does not play a role in skewing of X-inactivation. Expression of the Xist is negatively regulated by its antisense gene, Tsix. In order to determine the role of transcription in Tsix function, we modulated Tsix transcription with minimal disturbance of the genomic sequence. Loss of Tsix transcription lead to non-random inactivation of the targeted chromosome, whereas induction of Tsix expression caused the targeted chromosome always to be chosen as the active X. These results for the first time establish a function for antisense transcription in the regulation of Xist expression. The X-linked disease Rett syndrome (RTT), a neurodevelopmental disorder, is caused by mutations in the MECP2 gene. We used a mouse model to test the hypothesis that RTT is exclusively caused by neuronal MeCP2 deficiency. Expression of an Mecp2 transgene in postmitotic neurons resulted in symptoms of severe motor dysfunction. Transgene expression in Mecp2 mutant mice, however, rescued
by Sandra Luikenhuis.
Ph.D.
Nora, Elphège-Pierre. "Architecture chromosomique du locus Xic : implications pour la régulation de l'inactivation du chromosome X." Thesis, Paris 11, 2011. http://www.theses.fr/2011PA112130/document.
Full textEarly development of female mammals is accompanied by transcriptional inactivation of one of their two X chromosomes. This event is initiated following mono-allelic expression of the Xist non-coding RNA – what is achieved by the interplay of numerous cis-regulatory elements present within the X inactivation center (Xic), such as its repressive antisense Tsix. Our work aimed at throwing light on the structural landscape that underlies such long-range regulation. Characterization of the three-dimensional architecture of the Xic, by the means of Chromosome Conformation Capture (3C)-based techniques and in situ fluorescence hybridization (FISH), revealed that the respective promoters of Xist and Tsix contact many distal genomic elements within the Xic, and that at least one of such interacting region exerts long-range cis-transcriptional control. Noticeably, Xist and Tsix promoters associate with different sets of elements in their respective 5’ direction that are spread out over several hundreds of kilobases These experiments also revealed unforeseen properties of chromatin architecture. Indeed, the Xic appears to be partitioned in several sub-regions, each spanning between 200kb and 1Mb, inside which chromosomal interactions are preferentially established. The existence of these interaction domains integrates with other structural features of the genome, such as underlying chromatin composition and association with the nuclear lamina, but does not seem to directly depend on them. By analyzing chromosome conformation of the Xic during cell differentiation we document the robustness of this organizational principle, with the noticeable exception of the inactive X chromosome that assumes a folding pattern that is more random than its active homolog. Finally we also bring evidence that variability in the folding pattern of the two X chromosomes in the same cell brings each Tsix allele in association with different sets of chromosomal partners at a given moment, suggesting that the instantaneous structural environment of each allele at the onset of mono-allelic Xist up-regulation is different.By combining approaches at the scale of cell populations on the one hand, and at the single chromatin fiber level on the other, this study provides a first vision of the structural landscape in which Xist regulation takes place, and brings new insights concerning fundamental properties of chromosome organization in mammals
Ensminger, Alexander Wilson. "Autosomal random asynchronous replication is analogous to X-chromosome inactivation." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/34197.
Full textIncludes bibliographical references.
A number of mammalian genes are expressed from only one of two alleles in either an imprinted or random manner. Those belonging to the random class include X-linked genes subject to X inactivation, as well as a number of autosomal genes, including odorant receptors, immunoglobulins, T-cell receptors, interleukins, natural killer-cell receptors, and pheromone receptors. Random asynchronous replication of DNA in S-phase represents an epigenetic mark that often parallels monoallelic expression. All randomly monoallelically expressed genes discovered to date replicate asynchronously in S-phase, though not all of the genes contained within asynchronous domains are monoallelically expressed. The focus of my work has been on understanding this random choice that cells make between two sequence-identical alleles. Using two-color fluorescent in situ hybridization (FISH) analyses, the random asynchronous replication of a large number of human and mouse genes appears to be coordinated at the level of entire chromosomes. This regulatory scheme is reminiscent of random X-chromosome inactivation, the dosage compensation machinery in mammals. We have shown that autosomal coordination responds to trisomy in a fashion similar to X inactivation, with one copy of the trisomic chromosome marked for early replication and the other two rendered late replicating.
(cont.) These observations raise the intriguing possibility that the mechanistic underpinnings of X inactivation and autosomal coordination may also be similar. Furthermore, the existence of chromosome-wide epigenetic differentiation between autosomes has evolutionary implications concerning the establishment of X inactivation as the approach to mammalian dosage compensation. A crucial event in X inactivation is the random monoallelic expression of a noncoding RNA, Xist from one of the two X chromosomes. Noncoding RNA transcripts are enticing candidates for regulating chromatin structure within the mammalian nucleus. We have initiated a screen for novel nuclear, noncoding RNA transcripts. Using expression array profiling, we have identified several broadly expressed nuclear enriched transcripts. In addition to Xist, this approach identified two noncoding transcripts, NEATI and NEAT2 that are located near one another on human chromosome 1 I and chromosome 19 of mice. Using a variety of techniques, including RNA FISH and RNA-mediated interference, we have explored the potential regulatory functions of these transcripts.
by Alexander Wilson Ensminger.
Ph.D.
Liu, Mengning. "Evolutionary landscape of CpG island methylation in X chromosome inactivation." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611328.
Full textFarazmand, Ali. "X-inactive specific transcript (XIST) and X chromosome inactivation in the bovine species." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ56279.pdf.
Full textVigneau, Sébastien. "Etude fonctionnelle de l'inactivation du chromosome X au moyen de délétions ciblées dans le centre d'inactivation du chromosome X murin." Paris 6, 2007. http://www.theses.fr/2007PA066271.
Full textRoyce-Tolland, Morgan Elizabeth. "Investigation into the molecular mechanisms that control random X chromosome inactivation." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3378505.
Full textHore, Timothy Alexander, and timothy hore@anu edu au. "THE EVOLUTION OF GENOMIC IMPRINTING AND X CHROMOSOME INACTIVATION IN MAMMALS." The Australian National University. Research School of Biological Sciences, 2008. http://thesis.anu.edu.au./public/adt-ANU20081216.152553.
Full textYang, Christine. "DNA methylation demonstrates spread of X-chromosome inactivation to human transgenes." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/43045.
Full textRosspopoff, Olga. "Evolution of the human & mouse X-chromosome inactivation regulatory network." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC295.
Full textLong non-coding RNAs (lncRNAs) have emerged as the major output of mammalian transcriptomes. As of today, the function of the majority of lncRNAs remains largely enigmatic and importantly may be mediated by various entities such as the transcript itself, the act of transcription or key regulatory elements within the locus. A remarkable characteristic of lncRNAs is their poor evolutionary conservation, which raises the question of their contribution to species-specific regulatory mechanisms.X chromosome inactivation (XCI) is a paradigm for epigenetic processes mediated by lncRNA genes (LRGs) and a powerful model to explore their functional, mechanistic and evolutionary aspects. XCI is a process initiated early during embryonic development, which ensures the dosage compensation of X-linked genes between male and female in mammals. In the mouse, XCI is triggered by the combined action of several LRGs, among which Xist is the key regulator of the process. Xist is produced from a genomic region, the X-chromosome inactivation center (Xic), that is enriched for LRGs described either as positive or negative XCI regulators. In the present study, we investigated the evolutionary conservation of two candidate LRGs, JPX and FTX, and their contribution to XIST regulation in both human and mouse.In the mouse, we demonstrated that the Jpx RNA is required for proper Xist expression and acts as a post-transcriptional regulator of Xist, most likely by affecting its accumulation or stability. In striking contrast, in human, it is JPX transcription, but not the transcript itself, that controls the RNA Polymerase II (RNAPII) recruitment at XIST promoter. Accordingly, the two genes are interacting through local chromosome conformation, emphasized by RNAPII bridges in between the two loci. While the function of JPX/Jpx in promoting XIST/Xist accumulation is conserved between human and mouse, the underlying mechanisms diverge markedly. On the other hand, preliminary results on FTX function in human, suggest that it might be involved in XCI maintenance in human in very specific cellular contexts. Altogether, these results shed a new light on the functional evolution of XIST regulatory network between mouse and human that might be specifically adapted to XCI requirements in each species. This work highlights the functional plasticity of lncRNAs in evolution and how it might play important roles in species-specific mechanism of gene regulation
Hore, Timothy Alexander. "The evolution of genomic imprinting and X chromosome inactivation in mammals /." View thesis entry in Australian Digital Theses Program, 2008. http://thesis.anu.edu.au/public/adt-ANU20081216.152553/index.html.
Full textAmos-Landgraf, James. "A HUMAN POPULATION STUDY OF THE GENETIC CONTROL OF X-INACTIVATION." Case Western Reserve University School of Graduate Studies / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=case1089861669.
Full textHäfner, Sophia Julia. "Study of X-inactivation independent functions of the conserved long noncoding RNA Ftx." Paris 7, 2014. http://www.theses.fr/2014PA077015.
Full textMy PhD project focuses on the study of the long RNAnc Ftx, whose gene is located in the X chromosome inactivation center, a region rich in genes encoding long RNAncs and in charge of the inactivation process of one X chromosome in female mammals. The team has shown that the expression of Ftx favors the expression of the neighboring genes, conferring it the role of an activator of the inactivation process. Ftx is also expressed in the adult murine organism, more specifically in the brain, suggesting thus functions independent of the inactivation process. As a consequence, I focused on the potential implication of Ftx in de development and/or the functions of the brain. Ftx expression in the brain is relatively homogeneous among different regions, although it is established only during the postnatal period, between P7 and P21, when it increases suddenly. This period corresponds to an important phase of restructuring of the murine brain like myelination and synaptic reorganization. Thus it is conceivable that Ftx takes part in one of these processes. Using a cellular model based on wild-type and Ftx-deleted mouse embryonic stem cells? I developed a technique of in vitro neural differentiation. Although the lors of Ftx does not impact in a visible way on the neural differentiation potential of the cells, an analysis by microarray revealed that it causes the overexpression of several Hox genes. These combined results reinforce the initial hypothesis and lay numerous exciting tracks
Simpson, T. Ian T. Ian. "An investigation into the role of methylation in mammalian X-chromosome inactivation." Thesis, University of Oxford, 1999. http://ora.ox.ac.uk/objects/uuid:5fd37c27-af19-4bbd-92a7-4c5b846b3a31.
Full textRomer, Justyna Teodora. "Studies on the role of the Xist gene in X chromosome inactivation." Thesis, Institute of Cancer Research (University Of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391361.
Full textPollex, Tim. "Analysis of the role of nuclear organization during random X chromosome inactivation." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA112192.
Full textX-chromosome inactivation (XCI) ensures dosage compensation in female mammals. Random XCI is established in the epiblast of female mouse embryos and can be recapitulated in vitro in differentiating embryonic stem cells (ESCs). The major regulator of XCI is the long non-coding RNA Xist, which is expressed from the X-inactivation center (Xic), covers the chromosome in cis and initiates gene silencing. During XCI, the two X chromosomes are treated very differently, despite their homology and the fact that they reside in the same nucleus. Nuclear localization has been hypothesized to play a role in monoallelic gene regulation, not only during XCI but also in other contexts. For example, association with heterochromatin and homologous trans interactions (“pairing”) have been implicated in the establishment of monoallelic gene expression in lymphoid cells and transient pairing has been suggested to participate in symmetry breaking during random XCI. Using the bacterial tetO/tetR system to alter the subnuclear localization and environment of one or both Xics, we have tested the function of subnuclear localization and trans interactions between the Xic loci during initiation of XCI. Using stable expression and reversible binding of TetR fusion proteins (e.g. LaminB1, Cbx5) we show that binding of these proteins can induce local gene repression and chromatin changes, although this is not always associated with subnuclear relocalization. We further show that the forced association of the Xic with the nuclear envelope, does not impact on the choice-making process during XCI. In particular, tethering both Xics to the nuclear lamina during early ESC differentiation resulted in a substantial reduction of homologous pairing events, but had no obvious impact on the onset of random, monoallelic Xist expression. Taken together, our results suggest that nuclear localization and trans interactions of the Xic may be downstream events rather than causal in the regulation of the XCI process.Furthermore, we recruited CTCF, a protein suggested to be involved in structural organization of the genome, to the Xic using the tetO/tetR system. Upon binding of CTCF the overall structure of the Xic remained unaltered though few cis interactions appeared to be weakened, which was accompanied by gene repression in the Xic. Surprisingly, the only upregulated gene in the Xic was Xist in ESCs and during differentiation, which demonstrates that the induced minor changes of cis interactions might impact on gene regulation in the Xic
Csankovszki, Györgyi 1971. "The role of Xist RNA in the maintenance of X chromosome inactivation." Thesis, Massachusetts Institute of Technology, 2001. http://hdl.handle.net/1721.1/8209.
Full textIncludes bibliographical references.
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.
by Györgyi Csankovszki.
Ph.D.
Khalil, Ahmad M. "Histone modifications and chromatin dynamics of the mammalian inactive sex chromosomes title." [Gainesville, Fla.] : University of Florida, 2004. http://purl.fcla.edu/fcla/etd/UFE0008329.
Full textTypescript. Title from title page of source document. Document formatted into pages; contains 102 pages. Includes Vita. Includes bibliographical references.
Shen, Yin. "Regulation of DNA methylation and X chromosome inactivation in human embryonic stem cells." Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1709018911&sid=16&Fmt=2&clientId=1564&RQT=309&VName=PQD.
Full textChampion-Suntharalingam, K. M. "Aspects of molecular analysis in myeloproliferative disorders and myelodysplastic syndromes." Thesis, Anglia Ruskin University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342919.
Full textAugui, Sandrine. "Interactions chromosomiques et inactivation du chromosome X : éléments génétiques et mécanismes impliqués dans la reconnaissance du nombre de chromosomes X et dans la coordination des centres d'inactivation." Paris 11, 2009. http://www.theses.fr/2009PA112373.
Full textIn mammals, dosage compensation is achieved by the inactivation of one of the two X-chromosome during early development in females. X inactivation process is controlled by a complex locus, the X-inactivation centre (Xic), which includes the Xist gene and its antisense transcription unit Tsix/Xite. The Xic senses X chromosome number and initiates inactivation by triggering mono-allelic up-regulation of Xist RNA, and reciprocally, down-regulation of Tsix from one of the two X chromosomes in females. However, the mechanisms underlying sensing and reciprocal Xist/Tsix regulation remain obscure. We recently showed that a previously untested segment of the Xic, lying several hundred kilobases upstream of Xist and enriched in histone H3K27me3 and H3K9me2 marks, brings the two Xic's together prior to the onset of X inactivation (Augui et al, Science 318:1362, 2007). This X-pairing-region (Xpr) can autonomously drive Xic trans-interactions even as an ectopic single copy transgene. Furthermore its presence in male ES cells is selected against, suggesting that it may have a role in triggering Xist up regulation. We proposed that the pairwise interactions driven by this novel X-pairing-region (Xpr) of the Xic might enable a cell to sense that more than one X-chromosome is present in an XX cell, by activating biallelic Xist expression. Furthermore we believe that Xpr pairing then facilitates association between the Tsix/Xite regions, thus rendering biallelic Xist expression monoallelic. Finally, we think that Xpr could be the missing functional region of the Xic since Xpr + Xist/Tsix transgenes seem to recapitulate all Xic function in a male cell line
Prudhomme, Julie. "Étude de la reprogrammation du chromosome X dans les cellules souches embryonnaires et extra-embryonnaires au cours du développement préimplantatoire murin." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066486.
Full textIn female Mammals, the transcriptional silencing of one of the two X chromosomes during early embryogenesis compensates the dosage disequilibrium of X-linked genes between sexes. Random X chromosome inactivation occurs in the inner cell mass of the blastocyst and is maintained through adult life in the soma. In some Eutherian species including mice, extraembryonic tissues (trophectoderm and primitive endoderm) exhibit imprinted inactivation of the paternal X. The inactive state of the Xp can be extensively studied ex vivo in Trophoblast Stem (TS) cells derived from the trophectoderm. We were able to select from the general cell population, TS cells exhibiting partial reactivation of the Xp or showing a complete switch of imprinted X-inactivation pattern. This reveals an accrued epigenetic plasticity of imprinted X-inactivation in the trophectoderm as compared to random X-inactivation in the soma.Random X-chromosome inactivation is recapitulated during the differentiation of female Embryonic Stem (ES) cells – which serves as cellular model. This process is triggered by the cis-accumulation of Xist long non coding RNA molecules which create a nuclear repressive domain around the future inactive X chromosome. Before differentiation, the accumulation of Xist is repressed by another lncRNA, Tsix, that is transcribed antisense to Xist. In order to address the functional dynamics of Xist and Tsix RNAs, we inserted different types of tag sequences in the endogenous Xist/Tsix locus. Incorporated in the sense or antisense RNA, these tags are specifically recognized by fluorescent molecules, thereby allowing live cell imaging of these transcripts
Grön, M. (Mathias). "Effects of human X and Y chromosomes on oral and craniofacial morphology:studies of 46,XY females, 47,XYY males and 45,X/46,XX females." Doctoral thesis, University of Oulu, 1999. http://urn.fi/urn:isbn:9514253744.
Full textFurlan, Giulia. "Investigating the contribution of the non-coding gene Ftx to X-chromosome inactivation in mammals." Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCC191/document.
Full textX-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
Prudhomme, Julie. "Étude de la reprogrammation du chromosome X dans les cellules souches embryonnaires et extra-embryonnaires au cours du développement préimplantatoire murin." Electronic Thesis or Diss., Paris 6, 2014. http://www.theses.fr/2014PA066486.
Full textIn female Mammals, the transcriptional silencing of one of the two X chromosomes during early embryogenesis compensates the dosage disequilibrium of X-linked genes between sexes. Random X chromosome inactivation occurs in the inner cell mass of the blastocyst and is maintained through adult life in the soma. In some Eutherian species including mice, extraembryonic tissues (trophectoderm and primitive endoderm) exhibit imprinted inactivation of the paternal X. The inactive state of the Xp can be extensively studied ex vivo in Trophoblast Stem (TS) cells derived from the trophectoderm. We were able to select from the general cell population, TS cells exhibiting partial reactivation of the Xp or showing a complete switch of imprinted X-inactivation pattern. This reveals an accrued epigenetic plasticity of imprinted X-inactivation in the trophectoderm as compared to random X-inactivation in the soma.Random X-chromosome inactivation is recapitulated during the differentiation of female Embryonic Stem (ES) cells – which serves as cellular model. This process is triggered by the cis-accumulation of Xist long non coding RNA molecules which create a nuclear repressive domain around the future inactive X chromosome. Before differentiation, the accumulation of Xist is repressed by another lncRNA, Tsix, that is transcribed antisense to Xist. In order to address the functional dynamics of Xist and Tsix RNAs, we inserted different types of tag sequences in the endogenous Xist/Tsix locus. Incorporated in the sense or antisense RNA, these tags are specifically recognized by fluorescent molecules, thereby allowing live cell imaging of these transcripts
Ciaudo, Constance. "Caractérisation fonctionnelle de nouveaux facteurs trans impliqués dans le processus d'inactivation du chromosome X murin." Paris 7, 2006. http://www.theses.fr/2006PA077084.
Full textIn mammals, each cell of the female contains two X chromosomes and hence, potentially a double dose of ail X-linked genes when compared to XY males, who carry a single X chromosome. X-inactivation is the mechanism that ensures the dosage-compensation of X-linked gene products between the two sexes. X-inactivation is under the control of a specific region of the X chromosome, the X inactivation center (Xic), which contains the Xist gene encoding a large noncoding RNA transcript whose upregulation is critical to the initiation of X-inactivation. As an approach to the identification of some of the potential molecular players in this process we have performed comparative transcriptional profiling of mouse 6. 5 dpc (days post-coïtum) female and male embryos using a modified SAGE (Serial analysis of gene expression) technique which allows the analysis of small quantifies of biological material. At 6. 5 dpc, a moment when random X-inactivation of embryonic tissues has just been achieved, some two hundred transcripts that were significantly enriched in the female gastrula compared to its male counterpart could be identified. The validation of an association with the X-inactivation process of a subset of these transcripts has been studied, ex vivo, in differentiating female and male ES cells and in female ES cells. We identified the Eif1 gene involved in translation initiation and RNA degradation. We show here that female embryonic stem cell lines, silenced by RNA interference for the Eif1 gene, are unable to form Xist RNA domains upon differentiation and fail to undergo X-inactivation. To probe further an effect involving RNA degradation pathways, the inhibition by RNA interference of Rent1, a factor essentiel for nonsense-mediated decay and Exosc1O, a specific nuclear component of the exosome, was analysed and shown to similarly impair Xist upregulation and XCI. Inhibition of the function of one or other of these genes leads to a failure of the female cells to undergo X inactivation, suggesting that post-transcriptional nuclear mRNA degradation pathway(s) are essential for the regulation of Xist RNA metabolism and X chromosome inactivation process
Seriola, Petit Anna. "Pluripotent stem cells as research models: the examples of trinucleotide repeat instability and X-chromosome inactivation." Doctoral thesis, Universitat Autònoma de Barcelona, 2015. http://hdl.handle.net/10803/325148.
Full textDisease modelling is an essential tool for the understanding of human disease. Currently, much of the information we have on human diseases is based on animal models. However, animal models differ molecularly and phenotypically from humans, and are not always suitable to reproduce with fidelity human diseases. In the past decades, human pluripotent stem cells (hPSC) have emerged as an interesting option in the field of cellular modelling, this development recently having taken up much momentum. In this work, we aimed at characterizing hPSC as models for the study of Myotonic dystrophy type 1 (DM1) and Huntington’s disease (HD) trinucleotide repeat (TNR) instability and to investigate the status of the X-chromosome inactivation with an eye on using these cells as models for early human development. In the first part of our work, we observed a significant TNR instability for the DM1 locus in hESC, and that differentiation resulted in a stabilization of the repeat. This stabilization was concommitant with a downregulation of the mismatch repair (MMR). Our results were later replicated in hiPSC by other researchers, showing their reproducibility and suggesting they may be extrapolated to other hPSC lines worldwide. Regarding the HD repeat, we found it was very stable in all conditions studied, both in undifferentiated hESC and cells differentiated into osteogenic progenitor-like cells, teratoma cells and neural progenitors. This is in line with other studies showing that hESC show very limited TNR in the HD locus. On the other hand, some groups have now reported some instability of this locus in cells differentiated into the neuronal lineage. The instability seen in neuronal lineage in later studies, not in our study, is probably explained by the use of hPSC derived neurons more similar to the cells showing in vivo instability than the ones we were able to generate at the time of the study. In the second part of the thesis we studied the X-chromosome inactivation in 23 female hPSC lines. We found that hPSC rapidly progress from a XIST-dependent XCI state to a culture-adapted, XIST-independent XCI state with loss of repressive histone modifications and erosion of methylation. We also report a remarkably high incidence of non-random XCI patterns, and that this skewing of the methylation patterns is independent from the transition to the XIST-independent XCI state, the origin of the X chromosome or chromosomal aberrations. These results suggest that XCI skewing is possibly driven by the activation or repression of a specific allele on the X chromosome, conferring a growth or survival advantage to the cells. Overall, hPSC appear to be a good in vitro model for the study of both DM1 and HD TNR instability, as the repeat follows in vitro the same patterns as found in vivo, including its dependency of the MMR machinery, particularly in the case of DM1. However, our results on the study of the X chromosome inactivation (XCI) state suggest caution when using hPSC as early human developmental research models. The eroded state of XCI found in many of the hPSC lines, and the frequency of skewed XCI patterns suggests that these cells are not a good proxy to early embryonic cells, at least what XCI is concerned. Conversely, they may still provide an interesting model to study gene function and mechanisms implicated.
Bartlett, Molly Harding. "X chromosome inactivation and the Pgk-1 gene methylation and mapping studies using female embryonal carcinoma cells." Thesis, University of Ottawa (Canada), 1989. http://hdl.handle.net/10393/5445.
Full textPenny, Graeme Douglas. "Analysis of the role of Xist in X chromosome inactivation using targeted mutagenesis in embryonic stem cells." Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244103.
Full textGalupa, Rafael. "Exploring the structural and functional dynamics of the X-inactivation centre locus during development." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS305.
Full textMammalian gene regulatory landscapes rely on the folding of chromosomes in the recently discovered topologically associating domains (TADs), which ensure appropriate communication between cis-regulatory elements and their target promoters. The aim of my PhD project was to characterise the molecular mechanisms that govern this novel architecture and its functional importance in the context of a critical and developmentally regulated locus, the X-inactivation centre (Xic). The Xic contains the necessary elements to trigger X-chromosome inactivation, an epigenetic phenomenon that occurs during the development of female mammals to transcriptionally silence one of the X-chromosomes and equalise X-linked gene expression between sexes. The Xic is partitioned into at least two TADs, but its full extent is unknown. Here, I present a comprehensive functional analysis of different cis-regulatory elements within the Xic, including enhancer-like regions, long noncoding RNA loci and structural elements. Upon generating a series of mutant alleles in mice and murine embryonic stem cells, I characterised the impact of these genomic rearrangements in the structural and transcriptional landscape of the Xic and identified novel players in the regulation of this locus, including cis-acting elements conserved across placental mammals and structural elements critical for the insulation between the Xic TADs. I also found evidence for communication across TADs at this locus, which provides new insights into how regulatory landscapes can work during development. This study also extends our understanding of the rules governing the organisation of TADs and their chromatin loops in the context of mammalian gene regulation
Nos mamíferos, a regulação da expressão genética depende da organização tridimensional dos cromosomas, em particular ao nível da comunicação regulatória entre promotores e enhancers. A esta escala, descobriu-se recentemente que os cromossomas estão organizados em domínios de interações topológicas (conhecidos como TADs, no acrónimo inglês) que se pensa providenciarem uma base estrutural para as paisagens de regulação transcricional dos genes. O meu projecto de tese teve como objectivo caracterizar os mecanismos moleculares responsáveis por esta arquitectura e a sua importância funcional no contexto de um locus crítico para o desenvolvimento embrionário, o centro de inactivação do cromossoma X (Xic, acrónimo inglês). O Xic contém os elementos genéticos necessários e suficientes para iniciar a inactivação do cromossoma X, um fenómeno epigenético que ocorre durante o desenvolvimento das fêmeas de mamíferos para silenciar um dos cromosomas X e igualar a expressão dos genes do X entre indivíduos XX e XY. O Xic está organizado em pelo menos dois TADs, mas o seu intervalo genético completo permanece desconhecido. Apresento nesta tese uma análise funcional e detalhada de diferentes sequências reguladoras presentes no Xic, incluindo regiões do tipo enhancer, genes de ARNs não codificantes e elementos estruturais. Após a criação de diversos alelos mutantes (deleções, inserções, inversões) em ratinho e em células estaminais embrionárias, através das recentes técnicas de engenharia genética, TALENs e CRISPR/Cas9, caracterizei o impacto destes rearranjos genéticos na paisagem topológica e transcricional do Xic, o que permitiu a identificação de novos actores moleculares na regulação deste locus. Em particular, descobrimos sequências de regulação transcricional altamente conservadas em mamíferos placentários e elementos estruturais importantes para a formação da fronteira entre os dois TADs do Xic. Descrevo também evidência de que há comunicação entre os dois TADs neste locus, o que compromete os modelos actuais do modus operandis dos TADs, e por isso contribui para um novo nível de compreensão dos mecanismos que regulam a expressão genética durante o desenvolvimento
Studer, Tania [Verfasser], and Henrik [Akademischer Betreuer] Kaessmann. "The developmental sex-biased expression of genes escaping X chromosome inactivation across mammals / Tania Studer ; Betreuer: Henrik Kaessmann." Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1177044978/34.
Full textNora, Elphege-Pierre. "Architecture chromosique du locus Xic : implications pour la régulation de l'inactivation du chromosome X." Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00635540.
Full textCastagné, Raphaële. "Expression des gènes du chromosome X : approche intégrée par génomique et transcriptomique à haut-débit chez l'homme." Paris 6, 2011. http://www.theses.fr/2011PA066463.
Full textBouazzi, Habib. "Contribution à l'identification de nouveaux gènes impliqués dans la Déficience intellectuelle liée au Sexe(X-LID) par séquençage à haut débit de l’exome du chromosome X avec la technologie SOLiD." Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB009/document.
Full textX linked Intellectual deficiency (X - LID); formerly X-LMR (X Linked Mental Retardation) is a common pathology (3 % of the population). Intellectual Deficiency (ID) is the most frequent cause of serious handicap in children and young adults. Defining features of ID include an overall intelligence quotient (IQ) of less than 70 together with associated functional deficits in adaptive behavior (such as daily living, social and communication skills), which manifest before18 years of age. ID pathogenesis remains obscure and 50% of cases have no known cause. Ten percent of the intellectual intellectual deficiency would be related to genes located on the X chromosome, and subsequently inherited by affected boys. Among the 931 genes of the X chromosome, only 114 genes have been identified as X-LID genes. The last (SSR4 gene) was characterized in March 2014. At the time of the Next Generation Sequencing (NGS), the laboratory of molecular genetics of Necker hospital in Paris is equipped with a platform for the identification of human genetic mutation by high-throughput sequencing for the diagnosis of rare diseases. The objective of my thesis work was to seek new genes for X linked intellectual deficiency in families with non-syndromes cognitive disorder affected boys and to identify mutations in the genes that are already known and to discuss the genotype, phenotype correlation. The approach that I have used in this study is genetic diagnosis by high-throughput sequencing of chromosome X exomes of 20 subjects belonging to ten X-LID French families. The procedure is to capture and enrich the exome of the X chromosome of patients, then to sequence it in our platform with a high throughput sequencer of SOLid technology then analyze the results and retain that new mutations to discuss their pathogenity. This study has highlighted new mutations in 21 genes, including nine that are not yet described among the X-LID genes. Some new mutations, we identified in genes known through their involvement in cognitive impairment were published during my doctoral studies. To confirm causality of new genes that were found mutated in families, additional studies in vivo must be applied while following the literature to make comparisons with similar cases
Barros, de Andrade e. Sousa Lisa [Verfasser]. "Using interpretable machine learning to understand gene silencing dynamics during X-Chromosome inactivation / Lisa Barros de Andrade e Sousa." Berlin : Freie Universität Berlin, 2021. http://d-nb.info/1239115164/34.
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