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X-inactivation

About: X-inactivation is a(n) research topic. Over the lifetime, 2854 publication(s) have been published within this topic receiving 176534 citation(s).

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Journal ArticleDOI
Mary F. Lyon1Institutions (1)
22 Apr 1961-Nature
TL;DR: Ohno and Hauschka1 showed that in female mice one chromosome of mammary carcinoma cells and of normal diploid cells of the ovary, mammary gland and liver was heteropyKnotic and suggested that the so-called sex chromatin was composed of one heteropyknotic X-chromosome.

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Abstract: Ohno and Hauschka1 showed that in female mice one chromosome of mammary carcinoma cells and of normal diploid cells of the ovary, mammary gland and liver was heteropyknotic. They interpreted this chromosome as an X-chromosome and suggested that the so-called sex chromatin was composed of one heteropyknotic X-chromosome. They left open the question whether the heteropyknosis was shown by the paternal X-chromosome only, or the chromosome from either parent indifferently.

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3,499 citations


Journal ArticleDOI
Elphège P. Nora1, Bryan R. Lajoie2, Edda G. Schulz3, Luca Giorgetti1  +23 moreInstitutions (9)
17 May 2012-Nature
TL;DR: In addition to uncovering a new principle of cis-regulatory architecture of mammalian chromosomes, this study sets the stage for the full genetic dissection of the mouse X-inactivation centre.

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Abstract: High-order chromatin folding in topologically associating domains has a critical role in proper long-range transcriptional control around the Xist locus, and presumably throughout the genome. The spatial organization of the genome is linked to biological function, and advances in genomic technologies are allowing the conformation of chromosomes to be assessed genome wide. Two groups present complementary papers on the subject. Bing Ren and colleagues use Hi-C, an adaption of the chromosome conformation capture (3C) technique, to investigate the three-dimensional organization of the human and mouse genomes in embryonic stem cells and terminally differentiated cell types. Large, megabase-sized chromatin interaction domains, termed topological domains, are found to be a pervasive and conserved feature of genome organization. Edith Heard and colleagues use chromosome conformation capture carbon-copy (5C) technology and high-resolution microscopy to obtain a high-resolution map of the chromosomal interactions over a large region of the mouse X chromosome, including the X-inactivation centre. A series of discrete topologically associating domains is revealed, as is a previously unknown long intergenic RNA with a potential regulatory role. In eukaryotes transcriptional regulation often involves multiple long-range elements and is influenced by the genomic environment1. A prime example of this concerns the mouse X-inactivation centre (Xic), which orchestrates the initiation of X-chromosome inactivation (XCI) by controlling the expression of the non-protein-coding Xist transcript. The extent of Xic sequences required for the proper regulation of Xist remains unknown. Here we use chromosome conformation capture carbon-copy (5C)2 and super-resolution microscopy to analyse the spatial organization of a 4.5-megabases (Mb) region including Xist. We discover a series of discrete 200-kilobase to 1 Mb topologically associating domains (TADs), present both before and after cell differentiation and on the active and inactive X. TADs align with, but do not rely on, several domain-wide features of the epigenome, such as H3K27me3 or H3K9me2 blocks and lamina-associated domains. TADs also align with coordinately regulated gene clusters. Disruption of a TAD boundary causes ectopic chromosomal contacts and long-range transcriptional misregulation. The Xist/Tsix sense/antisense unit illustrates how TADs enable the spatial segregation of oppositely regulated chromosomal neighbourhoods, with the respective promoters of Xist and Tsix lying in adjacent TADs, each containing their known positive regulators. We identify a novel distal regulatory region of Tsix within its TAD, which produces a long intervening RNA, Linx. In addition to uncovering a new principle of cis-regulatory architecture of mammalian chromosomes, our study sets the stage for the full genetic dissection of the X-inactivation centre.

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2,191 citations


Journal ArticleDOI
Laura Carrel1, Huntington F. Willard2Institutions (2)
17 Mar 2005-Nature
TL;DR: A comprehensive X-inactivation profile of the human X chromosome is presented, representing an estimated 95% of assayable genes in fibroblast-based test systems, and suggests a remarkable and previously unsuspected degree of expression heterogeneity among females.

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Abstract: In female mammals, most genes on one X chromosome are silenced as a result of X-chromosome inactivation. However, some genes escape X-inactivation and are expressed from both the active and inactive X chromosome. Such genes are potential contributors to sexually dimorphic traits, to phenotypic variability among females heterozygous for X-linked conditions, and to clinical abnormalities in patients with abnormal X chromosomes. Here, we present a comprehensive X-inactivation profile of the human X chromosome, representing an estimated 95% of assayable genes in fibroblast-based test systems. In total, about 15% of X-linked genes escape inactivation to some degree, and the proportion of genes escaping inactivation differs dramatically between different regions of the X chromosome, reflecting the evolutionary history of the sex chromosomes. An additional 10% of X-linked genes show variable patterns of inactivation and are expressed to different extents from some inactive X chromosomes. This suggests a remarkable and previously unsuspected degree of expression heterogeneity among females.

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1,696 citations


Journal Article
R. C. Allen1, Huda Y. Zoghbi1, A. B. Moseley1, Howard M. Rosenblatt1  +1 moreInstitutions (1)
TL;DR: The human androgen-receptor gene (HUMARA) contains a highly polymorphic trinucleotide repeat in the first exon that correlates with X inactivation, and the development of a PCR assay that distinguishes between the maternal and paternal alleles and identifies their methylation status is developed.

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Abstract: The human androgen-receptor gene (HUMARA; GenBank) contains a highly polymorphic trinucleotide repeat in the first exon. We have found that the methylation of HpaII and HhaI sites less than 100 bp away from this polymorphic short tandem repeat (STR) correlates with X inactivation. The close proximity of the restriction-enzyme sites to the STR allows the development of a PCR assay that distinguishes between the maternal and paternal alleles and identifies their methylation status. The accuracy of this assay was tested on (a) DNA from hamster/human hybrid cell lines containing either an active or inactive human X chromosome; (b) DNA from normal males and females; and (c) DNA from females showing nonrandom patterns of X inactivation. Data obtained using this assay correlated substantially with those obtained using the PGK, HPRT, and M27 beta probes, which detect X inactivation patterns by Southern blot analysis. In order to demonstrate one application of this assay, we examined X inactivation patterns in the B lymphocytes of potential and obligate carriers of X-linked agammaglobulinemia.

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1,615 citations


Journal ArticleDOI
Jing Zhao1, Bryan K. Sun2, Bryan K. Sun1, Jennifer A. Erwin2  +4 moreInstitutions (2)
31 Oct 2008-Science
Abstract: To equalize X-chromosome dosages between the sexes, the female mammal inactivates one of her two X chromosomes. X-chromosome inactivation (XCI) is initiated by expression of Xist, a 17-kb noncoding RNA (ncRNA) that accumulates on the X in cis. Because interacting factors have not been isolated, the mechanism by which Xist induces silencing remains unknown. We discovered a 1.6-kilobase ncRNA (RepA) within Xist and identified the Polycomb complex, PRC2, as its direct target. PRC2 is initially recruited to the X by RepA RNA, with Ezh2 serving as the RNA binding subunit. The antisense Tsix RNA inhibits this interaction. RepA depletion abolishes full-length Xist induction and trimethylation on lysine 27 of histone H3 of the X. Likewise, PRC2 deficiency compromises Xist up-regulation. Therefore, RepA, together with PRC2, is required for the initiation and spread of XCI. We conclude that a ncRNA cofactor recruits Polycomb complexes to their target locus.

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1,476 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
2021102
202085
2019104
2018101
201788
2016109

Top Attributes

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Topic's top 5 most impactful authors

Edith Heard

93 papers, 12.6K citations

Jeannie T. Lee

84 papers, 13.7K citations

Carolyn J. Brown

63 papers, 7K citations

Neil Brockdorff

59 papers, 5.5K citations

Philip Avner

49 papers, 6.2K citations