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X chromosome inactivation

Salima El Chehadeh, Renaud Touraine, Fabienne Prieur, Willie Reardon, Thierry Bienvenu, Sandrine Chantot-Bastaraud, Martine Doco-Fenzy, Emilie Landais, Christophe Philippe, Nathalie Marle, Patrick Callier, Anne-Laure Mosca-Boidron, Francine Mugneret, Nathalie Le Meur, Alice Goldenberg, Anne-Marie Guerrot, Pascal Chambon, Véronique Satre, Charles Coutton, Pierre-Simon Jouk, Françoise Devillard, Klaus Dieterich, Alexandra Afenjar, Lydie Burglen, Marie-Laure Moutard, Marie-Claude Addor, Sébastien Lebon, Danielle Martinet, Jean-Luc Alessandri, Bérénice Doray, Marguerite Miguet, Didier Devys, Pascale Saugier-Veber, Séverine Drunat, Bernard Aral, Valérie Kremer, Stéphane Rondeau, Anne-Claude Tabet, Julien Thevenon, Christel Thauvin-Robinet, Nathalie Perreton, Vincent Des Portes, Laurence Faivre
Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling...
October 19, 2016: Clinical Genetics
Hai-Qiang Dai, Bang-An Wang, Lu Yang, Jia-Jia Chen, Guo-Chun Zhu, Mei-Ling Sun, Hao Ge, Rui Wang, Deborah L Chapman, Fuchou Tang, Xin Sun, Guo-Liang Xu
Mammalian genomes undergo epigenetic modifications, including cytosine methylation by DNA methyltransferases (DNMTs). Oxidation of 5-methylcytosine by the Ten-eleven translocation (TET) family of dioxygenases can lead to demethylation. Although cytosine methylation has key roles in several processes such as genomic imprinting and X-chromosome inactivation, the functional significance of cytosine methylation and demethylation in mouse embryogenesis remains to be fully determined. Here we show that inactivation of all three Tet genes in mice leads to gastrulation phenotypes, including primitive streak patterning defects in association with impaired maturation of axial mesoderm and failed specification of paraxial mesoderm, mimicking phenotypes in embryos with gain-of-function Nodal signalling...
October 19, 2016: Nature
Indhu-Shree Rajan-Babu, Samuel S Chong
Fragile X syndrome (FXS) is the most common monogenic cause of intellectual disability and autism. Molecular diagnostic testing of FXS and related disorders (fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS)) relies on a combination of polymerase chain reaction (PCR) and Southern blot (SB) for the fragile X mental retardation 1 (FMR1) CGG-repeat expansion and methylation analyses. Recent advancements in PCR-based technologies have enabled the characterization of the complete spectrum of CGG-repeat mutation, with or without methylation assessment, and, as a result, have reduced our reliance on the labor- and time-intensive SB, which is the gold standard FXS diagnostic test...
October 14, 2016: Genes
Geber Pena, Christina Michalski, Yong Qin, Robert Donnelly, Ziad Sifri, Anne Mosenthal, David Livingston, Zoltan Spolarics
Sex-related outcome disparities following severe trauma have been demonstrated in human and animal studies however sex hormone status could not fully account for the differences. This study tested whether X-linked cellular mosaicism, which is unique to females, could represent a genetically based mechanism contributing to sex-related immuno-modulation following trauma. Serial blood samples collected for routine laboratory tests were analyzed for ChrX inactivation (XCI) ratios in white blood cells. 39 severely injured (mean ISS 19) female trauma patients on mixed racial and ethnic background were tested for initial (baseline) and trauma-induced changes in XCI-ratios and their associations with severity of injury and clinical outcome...
September 29, 2016: Shock
Christina Loley, Maris Alver, Themistocles L Assimes, Andrew Bjonnes, Anuj Goel, Stefan Gustafsson, Jussi Hernesniemi, Jemma C Hopewell, Stavroula Kanoni, Marcus E Kleber, King Wai Lau, Yingchang Lu, Leo-Pekka Lyytikäinen, Christopher P Nelson, Majid Nikpay, Liming Qu, Elias Salfati, Markus Scholz, Taru Tukiainen, Christina Willenborg, Hong-Hee Won, Lingyao Zeng, Weihua Zhang, Sonia S Anand, Frank Beutner, Erwin P Bottinger, Robert Clarke, George Dedoussis, Ron Do, Tõnu Esko, Markku Eskola, Martin Farrall, Dominique Gauguier, Vilmantas Giedraitis, Christopher B Granger, Alistair S Hall, Anders Hamsten, Stanley L Hazen, Jie Huang, Mika Kähönen, Theodosios Kyriakou, Reijo Laaksonen, Lars Lind, Cecilia Lindgren, Patrik K E Magnusson, Eirini Marouli, Evelin Mihailov, Andrew P Morris, Kjell Nikus, Nancy Pedersen, Loukianos Rallidis, Veikko Salomaa, Svati H Shah, Alexandre F R Stewart, John R Thompson, Pierre A Zalloua, John C Chambers, Rory Collins, Erik Ingelsson, Carlos Iribarren, Pekka J Karhunen, Jaspal S Kooner, Terho Lehtimäki, Ruth J F Loos, Winfried März, Ruth McPherson, Andres Metspalu, Muredach P Reilly, Samuli Ripatti, Dharambir K Sanghera, Joachim Thiery, Hugh Watkins, Panos Deloukas, Sekar Kathiresan, Nilesh J Samani, Heribert Schunkert, Jeanette Erdmann, Inke R König
In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD...
October 12, 2016: Scientific Reports
Federica Federici, Aristea Magaraki, Evelyne Wassenaar, Catherina J H van Veen-Buurman, Christine van de Werken, Esther B Baart, Joop S E Laven, J Anton Grootegoed, Joost Gribnau, Willy M Baarends
In mouse female preimplantation embryos, the paternal X chromosome (Xp) is silenced by imprinted X chromosome inactivation (iXCI). This requires production of the noncoding Xist RNA in cis, from the Xp. The Xist locus on the maternally inherited X chromosome (Xm) is refractory to activation due to the presence of an imprint. Paternal inheritance of an Xist deletion (XpΔXist) is embryonic lethal to female embryos, due to iXCI abolishment. Here, we circumvented the histone-to-protamine and protamine-to-histone transitions of the paternal genome, by fertilization of oocytes via injection of round spermatids (ROSI)...
October 2016: PLoS Genetics
Rui Gao, Lan Wang, Hao Cai, Jingjing Zhu, Long Yu
RNF12/RLIM is a RING domain-containing E3 ubiquitin ligase whose function has only begun to be elucidated recently. Although RLIM was reported to play important roles in some biological processes such as imprinted X-chromosome inactivation and regulation of TGF-β pathway etc., other functions of RLIM are largely unknown. Here, we identified RLIM as a novel E3 ubiquitin ligase for c-Myc, one of the most frequently deregulated oncoproteins in human cancers. RLIM associates with c-Myc in vivo and in vitro independently of the E3 ligase activity of RLIM...
2016: PloS One
Kwong-Man Ng, Pamela Y Mok, Amy W Butler, Jenny C Y Ho, Shing-Wan Choi, Yee-Ki Lee, Wing-Hon Lai, Ka-Wing Au, Yee-Man Lau, Lai-Yung Wong, Miguel A Esteban, Chung-Wah Siu, Pak C Sham, Alan Colman, Hung-Fat Tse
BACKGROUND: -Danon disease is an X-linked disorder that leads to fatal cardiomyopathy, caused by a deficiency in lysosome-associated membrane protein-2 (LAMP2). In female patients, a later-onset and less severe clinical phenotype have been attributed to the random inactivation of the X-chromosome carrying the mutant diseased allele. We generated a patient-specific induced pluripotent stem cell (iPSCs) based model of Danon disease to evaluate the therapeutic potential of Xi-chromosome reactivation using a DNA methylation inhibitor...
September 27, 2016: Circulation
Claire Barnes, Aditi Kanhere
Recent advances in next-generation sequencing have revealed that majority of the human genome is transcribed into long and short RNA (ncRNA) transcripts. Many ncRNAs function by interacting with proteins and forming regulatory complexes. RNA-protein interactions are vital in controlling core cellular processes like transcription and translation. Therefore identifying proteins that interact with ncRNAs is central to deciphering ncRNA functions. Here we describe an RNA-protein pull-down assay, which enables the identification of proteins that interact with an RNA under study...
2016: Methods in Molecular Biology
Omkaram Gangisetty, Sengottuvelan Murugan
Epigenetic modifications, including DNA methylation, covalent histone modifications, and small noncoding RNAs, play a key role in regulating the gene expression. This regulatory mechanism is important in cellular differentiation and development. Recent advances in the field of epigenetics extended the role of epigenetic mechanisms in controlling key biological processes such as genome imprinting and X-chromosome inactivation. Aberrant epigenetic modifications are associated with the development of many diseases...
2016: Advances in Neurobiology
Feng Wang, JongDae Shin, Jeremy M Shea, Jun Yu, Ana Bošković, Meg Byron, Xiaochun Zhu, Alex K Shalek, Aviv Regev, Jeanne B Lawrence, Eduardo M Torres, Lihua J Zhu, Oliver J Rando, Ingolf Bach
Mammalian X-linked gene expression is highly regulated as female cells contain two and male one X chromosome (X). To adjust the X gene dosage between genders, female mouse preimplantation embryos undergo an imprinted form of X chromosome inactivation (iXCI) that requires both Rlim (also known as Rnf12) and the long non-coding RNA Xist. Moreover, it is thought that gene expression from the single active X is upregulated to correct for bi-allelic autosomal (A) gene expression. We have combined mouse genetics with RNA-seq on single mouse embryos to investigate functions of Rlim on the temporal regulation of iXCI and Xist...
September 19, 2016: ELife
Natália D Linhares, Eugênia R Valadares, Silvia S da Costa, Rodrigo R Arantes, Luiz Roberto de Oliveira, Carla Rosenberg, Angela M Vianna-Morgante, Marta Svartman
We report on a 16-year-old boy with a maternally inherited ~ 18.3 Mb Xq13.2-q21.31 duplication delimited by aCGH. As previously described in patients with similar duplications, his clinical features included intellectual disability, developmental delay, speech delay, generalized hypotonia, infantile feeding difficulties, self-injurious behavior, short stature and endocrine problems. As additional findings, he presented recurrent seizures and pubertal gynecomastia. His mother was phenotypically normal and had completely skewed inactivation of the duplicated X chromosome, as most female carriers of such duplications...
September 2016: Meta Gene
Adriana Di-Battista, Vera Ayres Meloni, Magnus Dias da Silva, Mariana Moysés-Oliveira, Maria Isabel Melaragno
In females carrying structural rearrangements of an X-chromosome, cells with the best dosage balance are preferentially selected, frequently resulting in a skewed inactivation pattern and amelioration of the phenotype. The Xp11.23-p11.22 region is involved in a recently described microduplication syndrome associated with severe clinical consequences in males and females, causing intellectual disability, behavior problems, epilepsy with electroencephalogram anomalies, minor facial anomalies, and early onset of puberty...
September 8, 2016: American Journal of Medical Genetics. Part A
Malgorzata Lenartowicz, Torben Moos, Mateusz Ogórek, Thomas G Jensen, Lisbeth B Møller
Deficiency of one of the copper transporters ATP7A and ATP7B leads to the rare X-linked disorder Menkes Disease (MD) or the rare autosomal disorder Wilson disease (WD), respectively. In order to investigate whether the ATP7A and the ATP7B genes may be transcriptionally regulated, we measured the expression level of the two genes at various concentrations of iron, copper, and insulin. Treating fibroblasts from controls or from individuals with MD or WD for 3 and 10 days with iron chelators revealed that iron deficiency led to increased transcript levels of both ATP7A and ATP7B...
2016: Frontiers in Molecular Neuroscience
Manuela Magarin, Herbert Schulz, Ludwig Thierfelder, Jörg-Detlef Drenckhahn
The postnatal mammalian heart is considered a terminally differentiated organ unable to efficiently regenerate after injury. In contrast, we have recently shown a remarkable regenerative capacity of the prenatal heart using myocardial tissue mosaicism for mitochondrial dysfunction in mice. This model is based on inactivation of the X-linked gene encoding holocytochrome c synthase (Hccs) specifically in the developing heart. Loss of HCCS activity results in respiratory chain dysfunction, disturbed cardiomyocyte differentiation and reduced cell cycle activity...
September 2016: Genomics Data
Matthew J Smola, Thomas W Christy, Kaoru Inoue, Cindo O Nicholson, Matthew Friedersdorf, Jack D Keene, David M Lee, J Mauro Calabrese, Kevin M Weeks
The 18-kb Xist long noncoding RNA (lncRNA) is essential for X-chromosome inactivation during female eutherian mammalian development. Global structural architecture, cell-induced conformational changes, and protein-RNA interactions within Xist are poorly understood. We used selective 2'-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP) to examine these features of Xist at single-nucleotide resolution both in living cells and ex vivo. The Xist RNA forms complex well-defined secondary structure domains and the cellular environment strongly modulates the RNA structure, via motifs spanning one-half of all Xist nucleotides...
September 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
Sonja Hombach, Markus Kretz
One of the long-standing principles of molecular biology is that DNA acts as a template for transcription of messenger RNAs, which serve as blueprints for protein translation. A rapidly growing number of exceptions to this rule have been reported over the past decades: they include long known classes of RNAs involved in translation such as transfer RNAs and ribosomal RNAs, small nuclear RNAs involved in splicing events, and small nucleolar RNAs mainly involved in the modification of other small RNAs, such as ribosomal RNAs and transfer RNAs...
2016: Advances in Experimental Medicine and Biology
Jialin Xu, Payal P Khincha, Neelam Giri, Blanche P Alter, Sharon A Savage, Judy M Y Wong
Dyskeratosis congenita (DC) is an inherited bone marrow failure and cancer susceptibility syndrome caused by germline mutations in telomere biology genes. Germline mutations in DKC1, which encodes the protein dyskerin, cause X-linked recessive DC. Due to skewed X-chromosome inactivation, female DKC1 mutation carriers do not typically develop clinical features of DC. This study evaluated female DKC1 mutation carriers with DC-associated phenotypes to elucidate the molecular features of their mutations, in comparison with unaffected carriers and mutation-negative female controls...
August 29, 2016: American Journal of Hematology
Fang Zeng, Zhihua Huang, Yujuan Yuan, Junsong Shi, Gengyuan Cai, Dewu Liu, Zhenfang Wu, Zicong Li
Xist is an X-linked gene responsible for cis induction of X chromosome inactivation. Studies have indicated that Xist is abnormally activated in the active X chromosome in cloned mouse embryos due to loss of the maternal Xist-repressing imprint following enucleation during somatic cell nuclear transfer (SCNT). Inhibition of Xist expression by injecting small interfering RNA (siRNA) has been shown to enhance the in vivo developmental efficiency of cloned male mouse embryos by more than 10-fold. The purpose of this study was to investigate whether a similar procedure can be applied to improve the cloning efficiency in pigs...
August 29, 2016: Journal of Reproduction and Development
Rita Ostan, Daniela Monti, Paola Gueresi, Mauro Bussolotto, Claudio Franceschi, Giovannella Baggio
Data showing a remarkable gender difference in life expectancy and mortality, including survival to extreme age, are reviewed starting from clinical and demographic data and stressing the importance of a comprehensive historical perspective and a gene-environment/lifestyle interaction. Gender difference regarding prevalence and incidence of the most important age-related diseases, such as cardiovascular and neurodegenerative diseases, cancer, Type 2 diabetes, disability, autoimmunity and infections, are reviewed and updated with particular attention to the role of the immune system and immunosenescence...
October 1, 2016: Clinical Science (1979-)
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