Systematic Allelic Analysis Defines the Interplay of Key Pathways in X Chromosome Inactivation

Mapping Intimacies ◽

10.1101/477232 ◽

2018 ◽

Author(s):

Tatyana B Nesterova ◽

Guifeng Wei ◽

Heather Coker ◽

Greta Pintacuda ◽

Joseph S Bowness ◽

...

Keyword(s):

X Chromosome ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Es Cell ◽

Systematic Analysis ◽

Relative Contribution ◽

Xist Rna ◽

A Minor ◽

In Cis ◽

Key Pathways

AbstractXist RNA, the master regulator of X chromosome inactivation, acts in cis to induce chromosome silencing through the stepwise recruitment of factors that modify underlying chromatin structure. Whilst considerable progress has been made towards defining key silencing factors and the elements to which they bind, their relative contribution to silencing different genes, and their relationship with one another is poorly understood. Here we describe a systematic analysis of Xist-mediated allelic silencing in ES cell-based models. We show that Spen, recruited through the Xist A-repeat, plays a central role, being critical for silencing of all except a subset of weakly expressed genes. Polycomb, recruited through the Xist B/C-repeat, also plays a key role, favouring silencing of genes with pre-existing H3K27me3 chromatin. LBR and the Rbm15/ m6A-methyltransferase complex, previously proposed to have a central role, make at most a minor contribution to gene silencing. We integrate our findings in a comprehensive model for Xist-mediated chromosome silencing.

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Localized accumulation of Xist RNA in X chromosome inactivation

Open Biology ◽

10.1098/rsob.190213 ◽

2019 ◽

Vol 9 (12) ◽

pp. 190213 ◽

Cited By ~ 2

Author(s):

Neil Brockdorff

Keyword(s):

X Chromosome ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

X Chromosomes ◽

Non Coding Rna ◽

Xist Rna ◽

Analogous Manner ◽

Mammalian Embryos ◽

Non Coding Rnas ◽

In Cis

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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Ectopic Splicing Disturbs the Function of Xist RNA to Establish the Stable Heterochromatin State

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.751154 ◽

2021 ◽

Vol 9 ◽

Author(s):

Ruka Matsuura ◽

Tatsuro Nakajima ◽

Saya Ichihara ◽

Takashi Sado

Keyword(s):

Gene Silencing ◽

X Chromosome ◽

Molecular Basis ◽

Essential Role ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Inactive State ◽

Xist Rna ◽

In Cis ◽

Insight Into

Non-coding Xist RNA plays an essential role in X chromosome inactivation (XCI) in female mammals. It coats the X chromosome in cis and mediates the recruitment of many proteins involved in gene silencing and heterochromatinization. The molecular basis of how Xist RNA initiates chromosomal silencing and what proteins participate in this process has been extensively studied and elucidated. Its involvement in the establishment and maintenance of the X-inactivated state is, however, less understood. The XistIVS allele we previously reported is peculiar in that it can initiate XCI but fails to establish the inactive state that is stably maintained and, therefore, may provide an opportunity to explore how Xist RNA contributes to establish a robust heterochromatin state. Here we demonstrate that ectopic splicing taking place to produce XistIVS RNA disturbs its function to properly establish stable XCI state. This finding warrants the potential of XistIVS RNA to provide further insight into our understanding of how Xist RNA contributes to establish sustainable heterochromatin.

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X-chromosome inactivation in XX androgenetic mouse embryos surviving implantation

Development ◽

10.1242/dev.127.19.4137 ◽

2000 ◽

Vol 127 (19) ◽

pp. 4137-4145 ◽

Cited By ~ 4

Author(s):

I. Okamoto ◽

S. Tan ◽

N. Takagi

Keyword(s):

X Chromosome ◽

Ectopic Expression ◽

Blastocyst Stage ◽

X Chromosome Inactivation ◽

X Inactivation ◽

Chromosome Inactivation ◽

Current View ◽

Replication Banding ◽

Xist Rna ◽

Morula Stage

Using genetic and cytogenetic markers, we assessed early development and X-chromosome inactivation (X-inactivation) in XX mouse androgenones produced by pronuclear transfer. Contrary to the current view, XX androgenones are capable of surviving to embryonic day 7.5, achieving basically random X-inactivation in all tissues including those derived from the trophectoderm and primitive endoderm that are characterized by paternal X-activation in fertilized embryos. This finding supports the hypothesis that in fertilized female embryos, the maternal X chromosome remains active until the blastocyst stage because of a rigid imprint that prevents inactivation, whereas the paternal X chromosome is preferentially inactivated in extra-embryonic tissues owing to lack of such imprint. In spite of random X-inactivation in XX androgenones, FISH analyses revealed expression of stable Xist RNA from every X chromosome in XX and XY androgenonetic embryos from the four-cell to morula stage. Although the occurrence of inappropriate X-inactivation was further suggested by the finding that Xist continues ectopic expression in a proportion of cells from XX and XY androgenones at the blastocyst and the early egg cylinder stage, a replication banding study failed to provide positive evidence for inappropriate X-inactivation at E6. 5.

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Impact of Xist RNA on chromatin modifications and transcriptional silencing maintenance at different stages of imprinted X chromosome inactivation in vole Microtus levis

Chromosoma ◽

10.1007/s00412-017-0650-9 ◽

2017 ◽

Vol 127 (1) ◽

pp. 129-139 ◽

Cited By ~ 4

Author(s):

Alexander I. Shevchenko ◽

Elena V. Grigor’eva ◽

Sergey P. Medvedev ◽

Irina S. Zakharova ◽

Elena V. Dementyeva ◽

...

Keyword(s):

X Chromosome ◽

Transcriptional Silencing ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Chromatin Modifications ◽

Xist Rna ◽

Microtus Levis

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Getting to the center of X-chromosome inactivation: the role of transgenesThis paper is one of a selection of papers published in this Special Issue, entitled 30th Annual International Asilomar Chromatin and Chromosomes Conference, and has undergone the Journal’s usual peer review process.

Biochemistry and Cell Biology ◽

10.1139/o09-040 ◽

2009 ◽

Vol 87 (5) ◽

pp. 759-766 ◽

Cited By ~ 3

Author(s):

Jakub Minks ◽

Carolyn J. Brown

Keyword(s):

X Chromosome ◽

Peer Review Process ◽

Regulatory Elements ◽

X Chromosome Inactivation ◽

X Inactivation ◽

Chromosome Inactivation ◽

Xist Expression ◽

Inactivation Center ◽

Xist Rna ◽

Epigenetic Phenomenon

X-chromosome inactivation is a fascinating epigenetic phenomenon that is initiated by expression of a noncoding (nc)RNA, XIST, and results in transcriptional silencing of 1 female X. The process requires a series of events that begins even before XIST expression, and culminates in an active and a silent X within the same nucleus. We will focus on the role that transgenic systems have served in the current understanding of the process of X-chromosome inactivation, both in the initial delineation of an active and inactive X, and in the function of the XIST RNA. X inactivation is strictly cis-limited; recent studies have revealed elements within the X-inactivation center, the region required for inactivation, that are critical for the initial regulation of Xist expression and chromosome pairing. It has been revealed that the X-inactivation center contains a remarkable compendium of cis-regulatory elements, ncRNAs, and trans-acting pairing regions. We review the functional componentry of the X-inactivation center and discuss experiments that helped to dissect the XIST/Xist RNA and its involvement in the establishment of facultative heterochromatin.

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