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Feng Wang, Kurtis N McCannell, Ana Bošković, Xiaochun Zhu, JongDae Shin, Jun Yu, Judith Gallant, Meg Byron, Jeanne B Lawrence, Lihua J Zhu, Stephen N Jones, Oliver J Rando, Thomas G Fazzio, Ingolf Bach
During female mouse embryogenesis, two forms of X chromosome inactivation (XCI) ensure dosage compensation from sex chromosomes. Beginning at the four-cell stage, imprinted XCI (iXCI) exclusively silences the paternal X (Xp), and this pattern is maintained in extraembryonic cell types. Epiblast cells, which give rise to the embryo proper, reactivate the Xp (XCR) and undergo a random form of XCI (rXCI) around implantation. Both iXCI and rXCI depend on the long non-coding RNA Xist. The ubiquitin ligase RLIM is required for iXCI in vivo and occupies a central role in current models of rXCI...
December 26, 2017: Cell Reports
Cuicui Lyu, Jun Shen, Jianping Zhang, Feng Xue, Xiaofan Liu, Wei Liu, Rongfeng Fu, Liyan Zhang, Huiyuan Li, Donglei Zhang, Xiaobing Zhang, Tao Cheng, Renchi Yang, Lei Zhang
Skewed X chromosome inactivation (XCI) is a rare reason for hemophilia B in females. It is indefinite whether X chromosome reactivation (XCR) would occur when cells of hemophilia B patients with skewed XCI were reprogrammed into induced pluripotent stem cells (iPSCs). In this study, we investigated a female hemophilia B patient with a known F9 gene mutation: c.676C>T, p.Arg226Trp. We demonstrated that skewed XCI was the pathogenesis of the patient, and we successfully generated numerous iPSC colonies of the patient from peripheral blood mononuclear cells (PBMNCs), which was the first time for generating hemophilia-specific iPSCs from PBMNCs...
July 1, 2017: Stem Cells and Development
Teresa Robert Finestra, Joost Gribnau
To ensure X-linked gene dosage compensation between females (XX) and males (XY), one X chromosome undergoes X chromosome inactivation (XCI) in female cells. This process is tightly regulated throughout development by many different factors, with Xist as a key regulator, encoding a long non-coding RNA, involved in establishment of several layers of repressive epigenetic modifications. Several recent studies on XCI focusing on identification and characterization of Xist RNA-protein interactors, revealed new factors involved in gene silencing, genome topology and nuclear membrane attachment, amongst others...
June 2017: Current Opinion in Cell Biology
Yasunao F Kamikawa, Mary E Donohoe
Epigenetic reprogramming is exemplified by the remarkable changes observed in cellular differentiation and X-chromosome inactivation (XCI) in mammalian female cells. Histone 3 lysine 27 trimethylation (H3K27me3) is a modification that suppresses gene expression in multiple contexts including embryonic stem cells (ESCs) and decorates the entire inactive X-chromosome. The conversion of female somatic cells to induced pluripotency is accompanied by X-chromosome reactivation (XCR) and H3K27me3 erasure. Here, we show that the H3K27-specific demethylase Utx regulates the expression of the master regulators for XCI and XCR: Prdm14, Tsix, and Xist...
2015: PloS One
Vincent Pasque, Jason Tchieu, Rahul Karnik, Molly Uyeda, Anupama Sadhu Dimashkie, Dana Case, Bernadett Papp, Giancarlo Bonora, Sanjeet Patel, Ritchie Ho, Ryan Schmidt, Robin McKee, Takashi Sado, Takashi Tada, Alexander Meissner, Kathrin Plath
Reprogramming to iPSCs resets the epigenome of somatic cells, including the reversal of X chromosome inactivation. We sought to gain insight into the steps underlying the reprogramming process by examining the means by which reprogramming leads to X chromosome reactivation (XCR). Analyzing single cells in situ, we found that hallmarks of the inactive X (Xi) change sequentially, providing a direct readout of reprogramming progression. Several epigenetic changes on the Xi occur in the inverse order of developmental X inactivation, whereas others are uncoupled from this sequence...
December 18, 2014: Cell
Bernhard Payer, Jeannie T Lee
X-chromosome inactivation (XCI) in female mammals is a dramatic example of epigenetic gene regulation, which entails the silencing of an entire chromosome through a wide range of mechanisms involving noncoding RNAs, chromatin-modifications, and DNA-methylation. While XCI is associated with the differentiated cell state, it is reversed by X-chromosome reactivation (XCR) ex vivo in pluripotent stem cells and in vivo in the early mouse embryo and the germline. Critical in the regulation of XCI vs. XCR is the X-inactivation center, a multigene locus on the X-chromosome harboring several long noncoding RNA genes including, most prominently, Xist and Tsix...
2014: RNA Biology
Bernhard Payer, Michael Rosenberg, Masashi Yamaji, Yukihiro Yabuta, Michiyo Koyanagi-Aoi, Katsuhiko Hayashi, Shinya Yamanaka, Mitinori Saitou, Jeannie T Lee
Transitions between pluripotent and differentiated states are marked by dramatic epigenetic changes. Cellular differentiation is tightly linked to X chromosome inactivation (XCI), whereas reprogramming to induced pluripotent stem cells (iPSCs) is associated with X chromosome reactivation (XCR). XCR reverses the silent state of the inactive X, occurring in mouse blastocysts and germ cells. In spite of its importance, little is known about underlying mechanisms. Here, we examine the role of the long noncoding Tsix RNA and the germline factor, PRDM14...
December 26, 2013: Molecular Cell
Shafagh Al Nadaf, Janine E Deakin, Clément Gilbert, Terence J Robinson, Jennifer A M Graves, Paul D Waters
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...
February 2012: Chromosoma
Alexander I Shevchenko, Irina S Zakharova, Eugeny A Elisaphenko, Nicolay N Kolesnikov, Siobhan Whitehead, Christine Bird, Mark Ross, Jennifer R Weidman, Randy L Jirtle, Tatiana V Karamysheva, Nicolay B Rubtsov, John L VandeBerg, Nina A Mazurok, Tatyana B Nesterova, Neil Brockdorff, Suren M Zakian
X inactivation, the transcriptional silencing of one of the two X chromosomes in female mammals, achieves dosage compensation of X-linked genes relative to XY males. In eutherian mammals X inactivation is regulated by the X-inactive specific transcript (Xist), a cis-acting non-coding RNA that triggers silencing of the chromosome from which it is transcribed. Marsupial mammals also undergo X inactivation but the mechanism is relatively poorly understood. We set out to analyse the X chromosome in Monodelphis domestica and Didelphis virginiana, focusing on characterizing the interval defined by the Chic1 and Slc16a2 genes that in eutherians flank the Xist locus...
2007: Chromosome Research
N Allaman-Pillet, A Djemaï, C Bonny, D F Schorderet
X chromosome inactivation in mammals requires the Xist gene, which is exclusively expressed from the inactive X chromosome (Xi). The large heterogeneous Xist nuclear RNA colocalizes with Xi, most likely through nuclear protein interactions. The 5' region of the Xist RNA contains a series of well-conserved tandem repeats known to bind heteronuclear proteins in vitro and to enhance human XIST transcription. We show in an in vitro system that the conserved repeat element located in the 5' region of the mouse Xist gene (Xcr) represses three X-linked genes but has no effect on the autosomal genes Aprt, Ins, and the viral SV40 gene...
2000: Gene Expression
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