X chromosome inactivation: new players in the initiation of gene silencing

X chromosome inactivation (XCI) is a dosage compensation process that was adopted by female mammals to balance gene dosage between XX females and XY males. XCI starts with the upregulation of the non-coding RNA Xist, after which most X-linked genes are silenced and acquire a repressive chromatin state. Even though the chromatin marks of the inactive X have been fairly well described, the mechanisms responsible for the initiation of XCI remain largely unknown. In this review, we discuss recent developments that revealed unexpected factors playing a role in XCI and that might be of crucial importance to understand the mechanisms responsible for the very first steps of this chromosome-wide gene-silencing event.

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Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22031114 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1114

Author(s):

Ali Youness ◽

Charles-Henry Miquel ◽

Jean-Charles Guéry

Keyword(s):

Autoimmune Diseases ◽

X Chromosome ◽

Gene Dosage ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

X Chromosomes ◽

Female Sex Hormones ◽

Inactive X Chromosome ◽

Immune Related Genes ◽

Female Specific

Women represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system, recent data suggest that female sex hormones are not the only cause of the female predisposition to autoimmunity. Besides sex steroid hormones, growing evidence points towards the role of X-linked genetic factors. In female mammals, one of the two X chromosomes is randomly inactivated during embryonic development, resulting in a cellular mosaicism, where about one-half of the cells in a given tissue express either the maternal X chromosome or the paternal one. X chromosome inactivation (XCI) is however not complete and 15 to 23% of genes from the inactive X chromosome (Xi) escape XCI, thereby contributing to the emergence of a female-specific heterogeneous population of cells with bi-allelic expression of some X-linked genes. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity still remains to be established, the cellular mosaicism resulting from XCI escape is likely to create a unique functional plasticity within female immune cells. Here, we review recent findings identifying key immune related genes that escape XCI and the relationship between gene dosage imbalance and functional responsiveness in female cells.

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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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Spen links RNA-mediated endogenous retrovirus silencing and X chromosome inactivation

eLife ◽

10.7554/elife.54508 ◽

2020 ◽

Vol 9 ◽

Author(s):

Ava C Carter ◽

Jin Xu ◽

Meagan Y Nakamoto ◽

Yuning Wei ◽

Brian J Zarnegar ◽

...

Keyword(s):

Gene Silencing ◽

X Chromosome ◽

Protein Interactions ◽

Sex Chromosome ◽

Embryonic Stem ◽

Structural Similarity ◽

Chromatin Accessibility ◽

Endogenous Retrovirus ◽

X Chromosome Inactivation ◽

Chromosome Inactivation

The Xist lncRNA mediates X chromosome inactivation (XCI). Here we show that Spen, an Xist-binding repressor protein essential for XCI , binds to ancient retroviral RNA, performing a surveillance role to recruit chromatin silencing machinery to these parasitic loci. Spen loss activates a subset of endogenous retroviral (ERV) elements in mouse embryonic stem cells, with gain of chromatin accessibility, active histone modifications, and ERV RNA transcription. Spen binds directly to ERV RNAs that show structural similarity to the A-repeat of Xist, a region critical for Xist-mediated gene silencing. ERV RNA and Xist A-repeat bind the RRM domains of Spen in a competitive manner. Insertion of an ERV into an A-repeat deficient Xist rescues binding of Xist RNA to Spen and results in strictly local gene silencing in cis. These results suggest that Xist may coopt transposable element RNA-protein interactions to repurpose powerful antiviral chromatin silencing machinery for sex chromosome dosage compensation.

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X-Chromosome Inactivation during Preimplantation Development and in Pluripotent Stem Cells

Cytogenetic and Genome Research ◽

10.1159/000508610 ◽

2020 ◽

Vol 160 (6) ◽

pp. 283-294 ◽

Cited By ~ 1

Author(s):

Paola Rebuzzini ◽

Maurizio Zuccotti ◽

Silvia Garagna

Keyword(s):

Stem Cells ◽

X Chromosome ◽

Dosage Compensation ◽

Pluripotent Stem Cells ◽

Mammalian Cells ◽

Gene Dosage ◽

X Chromosome Inactivation ◽

Preimplantation Development ◽

Chromosome Inactivation ◽

Transcriptional Gene Silencing

X dosage compensation between XX female and XY male mammalian cells is achieved by a process known as X-chromosome inactivation (XCI). XCI initiates early during preimplantation development in female cells, and it is subsequently stably maintained in somatic cells. However, XCI is a reversible process that occurs in vivo in the inner cell mass of the blastocyst, in primordial germ cells or in spermatids during reprogramming. Erasure of transcriptional gene silencing can occur though a mechanism named X-chromosome reactivation (XCR). XCI and XCR have been substantially deciphered in the mouse, whereas they still remain debated in the human. In this review, we summarized the recent advances in the knowledge of X-linked gene dosage compensation during mouse and human preimplantation development and in pluripotent stem cells.

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Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation

Nature Reviews Genetics ◽

10.1038/nrg3035 ◽

2011 ◽

Vol 12 (8) ◽

pp. 542-553 ◽

Cited By ~ 224

Author(s):

Anton Wutz

Keyword(s):

Gene Silencing ◽

X Chromosome ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Facultative Heterochromatin ◽

Heterochromatin Formation

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Integrated analysis of Xist upregulation and X-chromosome inactivation with single-cell and single-allele resolution

Nature Communications ◽

10.1038/s41467-021-23643-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Guido Pacini ◽

Ilona Dunkel ◽

Norbert Mages ◽

Verena Mutzel ◽

Bernd Timmermann ◽

...

Keyword(s):

Gene Silencing ◽

Single Cell ◽

X Chromosome ◽

Embryonic Stem ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Cellular Heterogeneity ◽

Integrated Analysis ◽

X Chromosomes ◽

Multiple Levels

AbstractTo ensure dosage compensation between the sexes, one randomly chosen X chromosome is silenced in each female cell in the process of X-chromosome inactivation (XCI). XCI is initiated during early development through upregulation of the long non-coding RNA Xist, which mediates chromosome-wide gene silencing. Cell differentiation, Xist upregulation and gene silencing are thought to be coupled at multiple levels to ensure inactivation of exactly one out of two X chromosomes. Here we perform an integrated analysis of all three processes through allele-specific single-cell RNA-sequencing. Specifically, we assess the onset of random XCI in differentiating mouse embryonic stem cells, and develop dedicated analysis approaches. By exploiting the inter-cellular heterogeneity of XCI onset, we identify putative Xist regulators. Moreover, we show that transient Xist upregulation from both X chromosomes results in biallelic gene silencing right before transitioning to the monoallelic state, confirming a prediction of the stochastic model of XCI. Finally, we show that genetic variation modulates the XCI process at multiple levels, providing a potential explanation for the long-known X-controlling element (Xce) effect, which leads to preferential inactivation of a specific X chromosome in inter-strain crosses. We thus draw a detailed picture of the different levels of regulation that govern the initiation of XCI. The experimental and computational strategies we have developed here will allow us to profile random XCI in more physiological contexts, including primary human cells in vivo.

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Integrated analysis of Xist upregulation and gene silencing at the onset of random X-chromosome inactivation at high temporal and allelic resolution

10.1101/2020.07.20.211573 ◽

2020 ◽

Author(s):

Guido Pacini ◽

Ilona Dunkel ◽

Norbert Mages ◽

Verena Mutzel ◽

Bernd Timmermann ◽

...

Keyword(s):

Gene Silencing ◽

X Chromosome ◽

Embryonic Stem ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Cellular Heterogeneity ◽

Integrated Analysis ◽

High Temporal Resolution ◽

Negative Feedback Regulation ◽

Multiple Levels

AbstractTo ensure dosage compensation between the sexes, one randomly chosen X chromosome is silenced in each female cell in the process of X-chromosome inactivation (XCI). XCI is initiated during early development through upregulation of the long non-coding RNA Xist, which mediates chromosome-wide gene silencing. Cell differentiation, Xist upregulation and silencing are thought to be coupled at multiple levels to ensure inactivation of exactly one out of two X chromosomes. Here we perform an integrated analysis of all three processes through allele-specific single-cell RNA-sequencing. Specifically, we assess the onset of random XCI with high temporal resolution in differentiating mouse embryonic stem cells, and develop dedicated analysis approaches. By exploiting the inter-cellular heterogeneity of XCI onset, we identify Nanog downregulation as its main trigger and discover additional putative Xist regulators. Moreover, we confirm several predictions of the stochastic model of XCI where monoallelic silencing is thought to be ensured through negative feedback regulation. Finally, we show that genetic variation modulates the XCI process at multiple levels, providing a potential explanation for the long-known Xce effect, which leads to preferential inactivation of a specific X chromosome in inter-strain crosses. We thus draw a detailed picture of the different levels of regulation that govern the initiation of XCI. The experimental and computational strategies we have developed here will allow us to profile random XCI in more physiological contexts, including primary human cells in vivo.

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Differentiation-dependent requirement of Tsix long non-coding RNA in imprinted X-chromosome inactivation

Nature Communications ◽

10.1038/ncomms5209 ◽

2014 ◽

Vol 5 (1) ◽

Cited By ~ 25

Author(s):

Emily Maclary ◽

Emily Buttigieg ◽

Michael Hinten ◽

Srimonta Gayen ◽

Clair Harris ◽

...

Keyword(s):

X Chromosome ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Non Coding Rna ◽

Long Non Coding Rna

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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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