X-chromosome inactivation: the molecular basis of silencing
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X-chromosome inactivation occurs randomly for one of the two X chromosomes in female cells during development. Inactivation occurs when RNA transcribed from the Xist gene on the X chromosome from which it is expressed spreads to coat the whole X chromosome. In the first issue of Epigenetics and Chromatin, Nesterova and colleagues investigate the role of the RNA interference pathway enzyme Dicer in DNA methylation of the Xist promoter.Keywords:
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Imprinted inactivation of the paternal X chromosome in marsupials is the primordial mechanism of dosage compensation for X-linked genes between females and males in Therians. In Eutherian mammals, X chromosome inactivation (XCI) evolved into a random process in cells from the embryo proper, where either the maternal or paternal X can be inactivated. However, species like mouse and bovine maintained imprinted XCI exclusively in extraembryonic tissues. The existence of imprinted XCI in humans remains controversial, with studies based on the analyses of only one or two X-linked genes in different extraembryonic tissues. Here we readdress this issue in human term placenta by performing a robust analysis of allele-specific expression of 22 X-linked genes, including XIST, using 27 SNPs in transcribed regions. We show that XCI is random in human placenta, and that this organ is arranged in relatively large patches of cells with either maternal or paternal inactive X. In addition, this analysis indicated heterogeneous maintenance of gene silencing along the inactive X, which combined with the extensive mosaicism found in placenta, can explain the lack of agreement among previous studies. Our results illustrate the differences of XCI mechanism between humans and mice, and highlight the importance of addressing the issue of imprinted XCI in other species in order to understand the evolution of dosage compensation in placental mammals.
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Sex chromosome dosage compensation in both eutherian and marsupial mammals is achieved by X chromosome inactivation (XCI)—transcriptional repression that silences one of the two X chromosomes in the somatic cells of females. We recently used RNA fluorescent in situ hybridization (FISH) to show, in individual nuclei, that marsupial X inactivation (in the absence of XIST) occurs on a gene-by-gene basis, and that escape from inactivation is stochastic and independent of gene location. In the absence of similar data from fibroblast cell lines of eutherian representatives, a meaningful comparison is lacking. We therefore used RNA-FISH to examine XCI in fibroblast cell lines obtained from three distantly related eutherian model species: African savannah elephant (Loxodonta africana), mouse (Mus musculus) and human (Homo sapiens). We show that, unlike the orthologous marsupial X, inactivation of the X conserved region (XCR) in eutherians generally is complete. Two-colour RNA-FISH on female human, mouse and elephant interphase nuclei showed that XCR loci have monoallelic expression in almost all nuclei. However, we found that many loci located in the evolutionarily distinct recently added region (XAR) displayed reproducible locus-specific frequencies of nuclei with either one or two active X alleles. We propose that marsupial XCI retains features of an ancient incomplete silencing mechanism that was augmented by the evolution of the XIST gene that progressively stabilized the eutherian XCR. In contrast, the recently added region of the eutherian X displays an incomplete inactivation profile similar to that observed on the evolutionarily distinct marsupial X and the independently evolved monotreme X chromosomes.
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Author(s): Goodrich, Leeanne | Advisor(s): Panning, Barbara | Abstract: In placental mammals, dosage compensation of the sex chromosomes isachieved through inactivation of one X chromosome in female cells. This Xchromosome inactivation (XCI) requires tight developmental regulation to ensure all butone X chromosome is silenced.At the center of this process is Xist, a long non-coding RNA. Upon differentiationof a female cell, Xist spreads in cis to coat and silence the inactive X chromosome.While upregulation of Xist, has been shown to be sufficient for X inactivation to occur,no one has thoroughly investigated whether Xist is necessary for the establishment of Xchromosome inactivation. In this thesis I provide evidence that Xist is not required fordosage compensation of the X chromosome during epiblast-like cell differentiation. Thisresult suggests Xist-independent silencing mechanisms for this essential process maybe in place.A 1-2 Mb region of the X chromosome, termed the X-inactivation center (Xic) isnecessary in two copies for XCI to occur, indicating it is necessary for cells to count thenumber of X chromosomes present. I delete one copy of the putative 2 Mb Xic in maleand female mouse embryonic stem cells and present evidence that this deletion is notwell tolerated, suggesting that this region requires finer resolution mapping to identifythe minimal element required for counting.Finally, I finish with a review which elaborates on studies that enlighten ourunderstanding of activators and repressors that control XCI. Our findings challengeexisting dogmas in the field and provide the foundation for future work focused onuncovering the molecular mechanisms behind Xist-independent silencing of the Xchromosome.
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X chromosome inactivation achieves dosage equivalence for most X-linked genes between the two X chromosomes in females and the single X chromosome in males. In this article the evidence for random inactivation of an X chromosome is reviewed, along with the exceptions that result in nonrandom inactivation. Another exception to X chromosome inactivation is the presence of genes that escape inactivation and are expressed from both the active and inactive X chromosomes. The phenotypic consequences of such expression from the inactive X chromosome are discussed. The major players in the process of inactivation are presented. Initiation of inactivation requires the functional RNA, XIST, and the subsequent stable inactivation of the X chromosome relies upon the recruitment of many other factors, the majority of which are generally associated with heterochromatin.
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Gene dosage
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