Fitting the Puzzle Pieces: the Bigger Picture of XCI

Maduro, Cheryl; Hoon, Bas de; Gribnau, Joost

doi:10.1016/j.tibs.2015.12.003

Cited by 22 publications

(29 citation statements)

References 80 publications

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“…J€ org Gromoll raised the issue of the increasing gap between the recent exciting gain of knowledge on the X chromosome with respect to X inactivation (Disteche & Berletch, 2015;Maduro et al, 2016), escapee genes, and their organ-specific expression pattern compared to the somewhat outdated genetic diagnosis of KS by karyotype analysis only. To close this gap and make use of the emerging new technologies and knowledge, it would be necessary to obtain more information on the origin and haplotype of the X chromosome.…”

Section: Genetic and Basic Researchmentioning

confidence: 99%

The Klinefelter syndrome: current management and research challenges

et al. 2016

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Section: Genetic and Basic Researchmentioning

confidence: 99%

The Klinefelter syndrome: current management and research challenges

et al. 2016

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“…XCI has been extensively studied using mouse models and occurs in two waves during early embryogenesis in females Lee 2011;Disteche 2012;Maduro et al 2016). Imprinted XCI is observed in preimplantation embryos and involves silencing of the paternal X chromosome (X P ) in all cells of the early embryo (Takagi and Sasaki 1975;West et al 1977;Takagi et al 1978).…”

mentioning

confidence: 99%

“…Xist RNA is transcribed exclusively from the future inactive X chromosome, coats the chromosome (Clemson et al 1996;Engreitz et al 2013;Simon et al 2013), and triggers formation of silent chromatin that is stably inherited through cell divisions Lee 2011;Disteche 2012;Maduro et al 2016). In the preimplantation embryo and the extraembryonic lineages, Xist is expressed only from the X P , in keeping with imprinted X P inactivation.…”

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confidence: 99%

Female mice lacking Xist RNA show partial dosage compensation and survive to term

et al. 2016

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X-chromosome inactivation (XCI) compensates for differences in X-chromosome number between male and female mammals. XCI is orchestrated by Xist RNA, whose expression in early development leads to transcriptional silencing of one X chromosome in the female. Knockout studies have established a requirement for Xist with inviability of female embryos that inherit an Xist deletion from the father. Here, we report that female mice lacking Xist RNA can, surprisingly, develop and survive to term. Xist-null females are born at lower frequency and are smaller at birth, but organogenesis is mostly normal. Transcriptomic analysis indicates significant overexpression of hundreds of X-linked genes across multiple tissues. Therefore, Xist-null mice can develop to term in spite of a deficiency of dosage compensation. However, the degree of X-autosomal dosage imbalance was less than anticipated (1.14-fold to 1.36-fold). Thus, partial dosage compensation can be achieved without Xist, supporting the idea of inherent genome balance. Nevertheless, to date, none of the mutant mice has survived beyond weaning stage. Sudden death is associated with failure of postnatal organ maturation. Our data suggest Xist-independent mechanisms of dosage compensation and demonstrate that small deviations from X-autosomal balance can have profound effects on overall fitness.

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“…Even though the mechanistic strategies are substantially different among species, considerable parallels are observed in the mechanisms by which dosage compensation is achieved. Based on the investigation in different models, XCI has three well-demarcated stages: initiation, establishment and maintenance [4] . Lack of molecular details has been a major roadblock in understanding how this complex process of XCI is regulated.…”

Section: Introductionmentioning

confidence: 99%

Novel molecular players of X chromosome inactivation: new technologies and new insights

Przanowski¹,

Wasko²,

Bhatnagar³

2018

JTGG

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The dosage compensation in placental mammals is achieved by silencing of one copy of the X chromosomes in a female cell by a process called X chromosome inactivation (XCI). XCI ensures equal gene dosage for X-linked genes between the two genders. Although the choice of X chromosome to be silenced is random, once the silencing of the X chromosome has been established, this process is highly regulated and maintained throughout subsequent cell divisions. A long non-coding RNA, Xist , and its interacting proteins execute this multistep process, but several of these regulatory proteins remain unidentified. Recent technological advances based on the genetic and proteomics screening have identified several new regulatory factors as well as dissected the molecular details of XCI regulation. Moreover, identification of regulators of XCI offers an opportunity to explore reactivation of the inactive X chromosome (Xi ) as a potential therapeutic strategy to treat X-linked diseases, like Rett syndrome. Here, we summarize recent reports that identified new regulatory proteins and RNA species playing a crucial role in Xist localization and spreading, recruitment of silencing machinery to the Xi , Xist interaction with chromatin, and structural organization of the Xi in the nuclei.

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Fitting the Puzzle Pieces: the Bigger Picture of XCI

Cited by 22 publications

References 80 publications

The Klinefelter syndrome: current management and research challenges

The Klinefelter syndrome: current management and research challenges

Female mice lacking Xist RNA show partial dosage compensation and survive to term

Novel molecular players of X chromosome inactivation: new technologies and new insights

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