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Xi AND Xist

Irene Cantone, Hakan Bagci, Dirk Dormann, Gopuraja Dharmalingam, Tatyana Nesterova, Neil Brockdorff, Claire Rougeulle, Celine Vallot, Edith Heard, Ronan Chaligne, Matthias Merkenschlager, Amanda G Fisher
Erasure of epigenetic memory is required to convert somatic cells towards pluripotency. Reactivation of the inactive X chromosome (Xi) has been used to model epigenetic reprogramming in mouse, but human studies are hampered by Xi epigenetic instability and difficulties in tracking partially reprogrammed iPSCs. Here we use cell fusion to examine the earliest events in the reprogramming-induced Xi reactivation of human female fibroblasts. We show that a rapid and widespread loss of Xi-associated H3K27me3 and XIST occurs in fused cells and precedes the bi-allelic expression of selected Xi-genes by many heterokaryons (30-50%)...
2016: Nature Communications
Luca Giorgetti, Bryan R Lajoie, Ava C Carter, Mikael Attia, Ye Zhan, Jin Xu, Chong Jian Chen, Noam Kaplan, Howard Y Chang, Edith Heard, Job Dekker
X-chromosome inactivation (XCI) involves major reorganization of the X chromosome as it becomes silent and heterochromatic. During female mammalian development, XCI is triggered by upregulation of the non-coding Xist RNA from one of the two X chromosomes. Xist coats the chromosome in cis and induces silencing of almost all genes via its A-repeat region, although some genes (constitutive escapees) avoid silencing in most cell types, and others (facultative escapees) escape XCI only in specific contexts. A role for Xist in organizing the inactive X (Xi) chromosome has been proposed...
July 28, 2016: Nature
Jianle Wang, Camille M Syrett, Marianne C Kramer, Arindam Basu, Michael L Atchison, Montserrat C Anguera
Females have a greater immunological advantage than men, yet they are more prone to autoimmune disorders. The basis for this sex bias lies in the X chromosome, which contains many immunity-related genes. Female mammals use X chromosome inactivation (XCI) to generate a transcriptionally silent inactive X chromosome (Xi) enriched with heterochromatic modifications and XIST/Xist RNA, which equalizes gene expression between the sexes. Here, we examine the maintenance of XCI in lymphocytes from females in mice and humans...
April 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
Kun Tan, Lei An, Kai Miao, Likun Ren, Zhuocheng Hou, Li Tao, Zhenni Zhang, Xiaodong Wang, Wei Xia, Jinghao Liu, Zhuqing Wang, Guangyin Xi, Shuai Gao, Linlin Sui, De-Sheng Zhu, Shumin Wang, Zhonghong Wu, Ingolf Bach, Dong-Bao Chen, Jianhui Tian
Dynamic epigenetic reprogramming occurs during normal embryonic development at the preimplantation stage. Erroneous epigenetic modifications due to environmental perturbations such as manipulation and culture of embryos during in vitro fertilization (IVF) are linked to various short- or long-term consequences. Among these, the skewed sex ratio, an indicator of reproductive hazards, was reported in bovine and porcine embryos and even human IVF newborns. However, since the first case of sex skewing reported in 1991, the underlying mechanisms remain unclear...
March 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
Jun Kang, Hee Jin Lee, Sun-Young Jun, Eun Su Park, Lee-So Maeng
BACKGROUND: Cancer-testis antigens (CTAs) are potential targets for cancer immunotherapy. Many CTAs are located on the X chromosome and are epigenetically regulated. Loss of X chromosome inactivation (XCI) is observed in breast and ovarian cancers and is thought to be related to the overexpression of CTAs. We investigated the relation between expression of CTAs and loss of XCI in endometrial cancer. MATERIALS AND METHODS: We used data generated by The Cancer Genome Atlas Genome Data Analysis Centers and data for Xist knockout mice available at the Gene Expression Omnibus...
2015: PloS One
Minghui Yue, John Lalith Charles Richard, Yuya Ogawa
There is increasing evidence for the emergence of long noncoding RNAs (lncRNAs) as important components, especially in the regulation of gene expression. In the event of X chromosome inactivation, robust epigenetic marks are established in a long noncoding Xist RNA-dependent manner, giving rise to a distinct epigenetic landscape on the inactive X chromosome (Xi). The X inactivation center (Xic) is essential for induction of X chromosome inactivation and harbors two topologically associated domains (TADs) to regulate monoallelic Xist expression: one at the noncoding Xist gene and its upstream region, and the other at the antisense Tsix and its upstream region...
January 2016: Biochimica et Biophysica Acta
Norishige Yamada, Yuko Hasegawa, Minghui Yue, Tomofumi Hamada, Shinichi Nakagawa, Yuya Ogawa
To equalize X-linked gene dosage between the sexes in mammalian females, Xist RNA inactivates one of the two X-chromosomes. Here, we report the crucial function of Xist exon 7 in X-inactivation. Xist exon 7 is the second-largest exon with a well-conserved repeat E in eutherian mammals, but its role is often overlooked in X-inactivation. Although female ES cells with a targeted truncation of the Xist exon 7 showed no significant differences in their Xist expression levels and RNA stability from control cells expressing wild-type Xist, compromised localization of Xist RNA and incomplete silencing of X-linked genes on the inactive X-chromosome (Xi) were observed in the exon 7-truncated mutant cells...
August 2015: PLoS Genetics
Hongjae Sunwoo, John Y Wu, Jeannie T Lee
X-chromosome inactivation (XCI) is initiated by the long noncoding RNA Xist, which coats the inactive X (Xi) and targets Polycomb repressive complex 2 (PRC2) in cis. Epigenomic analyses have provided significant insight into Xist binding patterns and chromatin organization of the Xi. However, such epigenomic analyses are limited by averaging of population-wide dynamics and do not inform behavior of single cells. Here we view Xist RNA and the Xi at 20-nm resolution using STochastic Optical Reconstruction Microscopy (STORM) in mouse cells...
August 4, 2015: Proceedings of the National Academy of Sciences of the United States of America
Anand Minajigi, John E Froberg, Chunyao Wei, Hongjae Sunwoo, Barry Kesner, David Colognori, Derek Lessing, Bernhard Payer, Myriam Boukhali, Wilhelm Haas, Jeannie T Lee
The inactive X chromosome (Xi) serves as a model to understand gene silencing on a global scale. Here, we perform "identification of direct RNA interacting proteins" (iDRiP) to isolate a comprehensive protein interactome for Xist, an RNA required for Xi silencing. We discover multiple classes of interactors-including cohesins, condensins, topoisomerases, RNA helicases, chromatin remodelers, and modifiers-that synergistically repress Xi transcription. Inhibiting two or three interactors destabilizes silencing...
July 17, 2015: Science
Zhifu Sun, Naresh Prodduturi, Susan Y Sun, E Aubrey Thompson, Jean-Pierre A Kocher
AIM: Abnormal inactivation or loss of inactivated X chromosome (Xi) is implicated in women's cancer. However, the underlying mechanisms and clinical relevance are little known. MATERIALS & METHODS: High-throughput sequencing was conducted on breast cancer cell lines for copy number, RNA expression and 5'-methylcytosine in ChrX. The results were examined in primary breast tumors. RESULTS & CONCLUSION: Breast cancer cells demonstrated reduced or total loss of hemimethylation...
October 2015: Epigenomics
John Lalith Charles Richard, Yuya Ogawa
Balanced gene expression is a high priority in order to maintain optimal functioning since alterations and variations could result in acute consequences. X chromosome inactivation (X-inactivation) is one such strategy utilized by mammalian species to silence the extra X chromosome in females to uphold a similar level of expression between the two sexes. A functionally versatile class of molecules called long noncoding RNA (lncRNA) has emerged as key regulators of gene expression and plays important roles during development...
2016: Current Topics in Microbiology and Immunology
Céline Vallot, Jean-François Ouimette, Mélanie Makhlouf, Olivier Féraud, Julien Pontis, Julien Côme, Cécile Martinat, Annelise Bennaceur-Griscelli, Marc Lalande, Claire Rougeulle
Human pluripotent stem cells (hPSCs) display extensive epigenetic instability, particularly on the X chromosome. In this study, we show that, in hPSCs, the inactive X chromosome has a specific heterochromatin landscape that predisposes it to erosion of X chromosome inactivation (XCI), a process that occurs spontaneously in hPSCs. Heterochromatin remodeling and gene reactivation occur in a non-random fashion and are confined to specific H3K27me3-enriched domains, leaving H3K9me3-marked regions unaffected. Using single-cell monitoring of XCI erosion, we show that this instability only occurs in pluripotent cells...
May 7, 2015: Cell Stem Cell
Yilong Yao, Jun Ma, Yixue Xue, Ping Wang, Zhen Li, Jing Liu, Liangyu Chen, Zhuo Xi, Hao Teng, Zhenhua Wang, Zhiqing Li, Yunhui Liu
Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Great interest persists in useful therapeutic targets in GBM. Aberrant expression of long non-coding RNAs (lncRNAs) has been functionally associated with many cancers. Here, we elucidated the function and the possible molecular mechanisms of lncRNA XIST in human glioblastoma stem cells (GSCs). Our results proved that XIST expression was up-regulated in glioma tissues and GSCs. Functionally, knockdown of XIST exerted tumor-suppressive functions by reducing cell proliferation, migration and invasion as well as inducing apoptosis...
April 1, 2015: Cancer Letters
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
Minghui Yue, John Lalith Charles Richard, Norishige Yamada, Akiyo Ogawa, Yuya Ogawa
Combining RNA fluorescent in situ hybridization (FISH) with immunofluorescence (immuno-FISH) creates a technique that can be employed at the single cell level to detect the spatial dynamics of RNA localization with simultaneous insight into the localization of proteins, epigenetic modifications and other details which can be highlighted by immunofluorescence. X-chromosome inactivation is a paradigm for long non-coding RNA (lncRNA)-mediated gene silencing. X-inactive specific transcript (Xist) lncRNA accumulation (called an Xist cloud) on one of the two X-chromosomes in mammalian females is a critical step to initiate X-chromosome inactivation...
2014: Journal of Visualized Experiments: JoVE
Satya Keerthi Kota, Debabani Roy Chowdhury, Lakshmi K Rao, Venkata Padmalatha, Lalji Singh, Utpal Bhadra
In mammals, X-inactivation process is achieved by the cis-spreading of long noncoding Xist RNA over one of the female X chromosomes. The Xist binding accumulates histones H3 methylation and H4 hypoacetylation required for X inactivation that leads to proper dosage compensation of the X-linked genes. Co-transcription of Tsix, an antisense copy of Xist, blocks the Xist coating on the Xi. In mice ES cells, an RNase III enzyme Dicer1 disrupts Xist binding and methylated H3K27me3 accumulation on the Xi. Later, multiple reports opposed these findings raising a question regarding the possible role of Dicer1 in murine X silencing...
June 2015: Chromosoma
Jong Soo Kim, Hyun Woo Choi, Marcos J Araúzo-Bravo, Hans R Schöler, Jeong Tae Do
Direct reprogramming of somatic cells to pluripotent stem cells entails the obliteration of somatic cell memory and the reestablishment of epigenetic events. Induced pluripotent stem cells (iPSCs) have been created by reprogramming somatic cells through the transduction of reprogramming factors. During cell reprogramming, female somatic cells must overcome at least one more barrier than male somatic cells in order to enter a pluripotent state, as they must reactivate an inactive X chromosome (Xi). In this study, we investigated whether the sex of somatic cells affects reprogramming efficiency, differentiation potential and the post-transcriptional processing of Xist RNA after reprogramming...
January 1, 2015: Journal of Cell Science
Sanchita Bhatnagar, Xiaochun Zhu, Jianhong Ou, Ling Lin, Lynn Chamberlain, Lihua J Zhu, Narendra Wajapeyee, Michael R Green
X-chromosome inactivation (XCI), the random transcriptional silencing of one X chromosome in somatic cells of female mammals, is a mechanism that ensures equal expression of X-linked genes in both sexes. XCI is initiated in cis by the noncoding Xist RNA, which coats the inactive X chromosome (Xi) from which it is produced. However, trans-acting factors that mediate XCI remain largely unknown. Here, we perform a large-scale RNA interference screen to identify trans-acting XCI factors (XCIFs) that comprise regulators of cell signaling and transcription, including the DNA methyltransferase, DNMT1...
September 2, 2014: Proceedings of the National Academy of Sciences of the United States of America
Daniel Smeets, Yolanda Markaki, Volker J Schmid, Felix Kraus, Anna Tattermusch, Andrea Cerase, Michael Sterr, Susanne Fiedler, Justin Demmerle, Jens Popken, Heinrich Leonhardt, Neil Brockdorff, Thomas Cremer, Lothar Schermelleh, Marion Cremer
BACKGROUND: A Xist RNA decorated Barr body is the structural hallmark of the compacted inactive X territory in female mammals. Using super-resolution three-dimensional structured illumination microscopy (3D-SIM) and quantitative image analysis, we compared its ultrastructure with active chromosome territories (CTs) in human and mouse somatic cells, and explored the spatio-temporal process of Barr body formation at onset of inactivation in early differentiating mouse embryonic stem cells (ESCs)...
2014: Epigenetics & Chromatin
Alissa Minkovsky, Anna Sahakyan, Elyse Rankin-Gee, Giancarlo Bonora, Sanjeet Patel, Kathrin Plath
BACKGROUND: X chromosome inactivation (XCI) is a developmental program of heterochromatin formation that initiates during early female mammalian embryonic development and is maintained through a lifetime of cell divisions in somatic cells. Despite identification of the crucial long non-coding RNA Xist and involvement of specific chromatin modifiers in the establishment and maintenance of the heterochromatin of the inactive X chromosome (Xi), interference with known pathways only partially reactivates the Xi once silencing has been established...
2014: Epigenetics & Chromatin
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