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Unraveling the role of Xist in X chromosome inactivation: insights from rabbit model and deletion analysis of exons and repeat A.

ABSTRACT: X chromosome inactivation (XCI) is a process that equalizes the expression of X-linked genes between males and females. It relies on Xist, continuously expressed in somatic cells during XCI maintenance. However, how Xist impacts XCI maintenance and its functional motifs remain unclear. In this study, we conducted a comprehensive analysis of Xist, using rabbits as an ideal non-primate model. Homozygous knockout of exon 1, exon 6, and repeat A in female rabbits resulted in embryonic lethality. However, X^∆ReAX females, with intact X chromosome expressing Xist, showed no abnormalities. Interestingly, there were no significant differences between females with homozygous knockout of exons 2-5 and wild-type rabbits, suggesting that exons 2, 3, 4, and 5 are less important for XCI. These findings provide evolutionary insights into Xist function.

SUBMITTER: Liang M

PROVIDER: S-EPMC10980640 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Unraveling the role of Xist in X chromosome inactivation: insights from rabbit model and deletion analysis of exons and repeat A.

Liang Mingming M Zhang Lichao L Lai Liangxue L Li Zhanjun Z

Cellular and molecular life sciences : CMLS 20240329 1

X chromosome inactivation (XCI) is a process that equalizes the expression of X-linked genes between males and females. It relies on Xist, continuously expressed in somatic cells during XCI maintenance. However, how Xist impacts XCI maintenance and its functional motifs remain unclear. In this study, we conducted a comprehensive analysis of Xist, using rabbits as an ideal non-primate model. Homozygous knockout of exon 1, exon 6, and repeat A in female rabbits resulted in embryonic lethality. How ...[more]

PMID: 38551746

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D-repeat in the XIST gene is required for X chromosome inactivation.

Project description:XIST is a long non-coding RNA, which expressed exclusively from the inactive X chromosome. Although it has been revealed that the A-repeat contributes to the X chromosome inactivation (X-inactivation), the role of the longest D-repeat has not yet been investigated. Here, a sgRNA directed CRISPR/Cas9 system which have multiple target sites within repeat D of XIST, were used to generate D-repeat deletion and studied its roles on X-inactivation. The results showed that the deletion of D-repeat caused a significantly decreased expression of XIST, and up regulated expression of X-linked genes, suggesting that the D-repeat may play an important role in the regulation of XIST expression and silencing of the X-linked genes, which could provide a new idea in the molecular mechanisms of X-inactivation.

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Project description:This SuperSeries is composed of the SubSeries listed below.

2019-06-17 | GSE119607 | GEO

Localized accumulation of Xist RNA in X chromosome inactivation.

Project description:The non-coding RNA Xist regulates the process of X chromosome inactivation, in which one of the two X chromosomes present in cells of early female mammalian embryos is selectively and coordinately shut down. Remarkably Xist RNA functions in cis, affecting only the chromosome from which it is transcribed. This feature is attributable to the unique propensity of Xist RNA to accumulate over the territory of the chromosome on which it is synthesized, contrasting with the majority of RNAs that are rapidly exported out of the cell nucleus. In this review I provide an overview of the progress that has been made towards understanding localized accumulation of Xist RNA, drawing attention to evidence that some other non-coding RNAs probably function in a highly analogous manner. I describe a simple model for localized accumulation of Xist RNA and discuss key unresolved questions that need to be addressed in future studies.

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Project description:Xist-mediated Chromosome Inactivation

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An Xist-activating antisense RNA required for X-chromosome inactivation.

Project description:The transcriptional imbalance due to the difference in the number of X chromosomes between male and female mammals is remedied through X-chromosome inactivation, the epigenetic transcriptional silencing of one of the two X chromosomes in females. The X-linked Xist long non-coding RNA functions as an X inactivation master regulator; Xist is selectively upregulated from the prospective inactive X chromosome and is required in cis for X inactivation. Here we discover an Xist antisense long non-coding RNA, XistAR (Xist Activating RNA), which is encoded within exon 1 of the mouse Xist gene and is transcribed only from the inactive X chromosome. Selective truncation of XistAR, while sparing the overlapping Xist RNA, leads to a deficiency in Xist RNA expression in cis during the initiation of X inactivation. Thus, the Xist gene carries within its coding sequence an antisense RNA that drives Xist expression.

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The role of Xist-mediated Polycomb recruitment in the initiation of X-chromosome inactivation

Project description:Xist RNA has been established as the master regulator of X-chromosome inactivation (XCI) in female eutherian mammals but its mechanism of action remains unclear. By creating novel Xist inducible mutants at the endogenous locus in male mouse embryonic stem (ES) cells, we dissect the role of the conserved A-B-C-F repeats in the initiation of XCI. We find that transcriptional silencing can be largely uncoupled from Polycomb repressive complex 1 and 2 (PRC1/2) recruitment, which requires B and C repeats. Xist ?B+C RNA specifically loses interaction with PCGF3/5 subunits of PRC1, while binding of other Xist partners is largely unaffected. However, a slight relaxation of transcriptional silencing in Xist ?B+C indicates a role for PRC1/2 proteins in early stabilization of gene repression. Distinct modules within the Xist RNA are therefore involved in the convergence of independent chromatin modification and gene repression pathways. In this context, Polycomb recruitment seems to be of moderate relevance in the initiation of silencing.

| S-SCDT-EMBOR-2019-48019V1 | biostudies-other

The role of Xist-mediated Polycomb recruitment in the initiation of X-chromosome inactivation

Project description:The role of Xist-mediated Polycomb recruitment in the initiation of X-chromosome inactivation

2019-08-29 | PXD014287 | Pride

Evidence of Xist RNA-independent initiation of mouse imprinted X-chromosome inactivation.

Project description:XX female mammals undergo transcriptional silencing of most genes on one of their two X chromosomes to equalize X-linked gene dosage with XY males in a process referred to as X-chromosome inactivation (XCI). XCI is an example of epigenetic regulation. Once enacted in individual cells of the early female embryo, XCI is stably transmitted such that most descendant cells maintain silencing of that X chromosome. In eutherian mammals, XCI is thought to be triggered by the expression of the non-coding Xist RNA from the future inactive X chromosome (Xi); Xist RNA in turn is proposed to recruit protein complexes that bring about heterochromatinization of the Xi. Here we test whether imprinted XCI, which results in preferential inactivation of the paternal X chromosome (Xp), occurs in mouse embryos inheriting an Xp lacking Xist. We find that silencing of Xp-linked genes can initiate in the absence of paternal Xist; Xist is, however, required to stabilize silencing along the Xp. Xp-linked gene silencing associated with mouse imprinted XCI, therefore, can initiate in the embryo independently of Xist RNA.

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