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Xist RNA targets selective autosomal genes to modulate expression in a Repeat B-dependent manner [RNA-seq]

ABSTRACT: Xist, a pivotal player in X chromosome inactivation (XCI), has long been perceived as a cis-acting long noncoding RNA that binds exclusively to the inactive X chromosome (Xi). However, Xist’s ability to diffuse under select circumstances has long been documented, leading us to suspect that Xist RNA may have targets and functions beyond the Xi. Here, using female mouse embryonic stem cells (ES) and mouse embryonic fibroblasts (MEF) as a model, we demonstrate that Xist RNA indeed can spread beyond the Xi. However, its binding is limited to ~100 genes in differentiating ES and MEF cells. The target genes are diverse in function but are unified by their active chromatin status. Although active, Xist binding is associated with a downregulation of gene expression. Unlike on the Xi, Xist binding does not lead to full silencing and also does not spread beyond the target gene. Deleting Xist’s Repeat B (RepB) domain reduces Xist’s diffusion away from the Xi and inhibits Xist’s localization to autosomal targets. Nonetheless, Xist transcript lacking RepB fails to down-modulate autosomal gene expression. Altogether, our findings reveal Xist targets beyond the Xi and identify Repeat B as a crucial domain for its in-trans function.

ORGANISM(S): Mus musculus

PROVIDER: GSE271097 | GEO | 2024/08/23

REPOSITORIES: GEO

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Xist RNA targets selective autosomal genes to modulate expression in a Repeat B-dependent manner [CHART-seq]

Project description:Xist, a pivotal player in X chromosome inactivation (XCI), has long been perceived as a cis-acting long noncoding RNA that binds exclusively to the inactive X chromosome (Xi). However, Xist’s ability to diffuse under select circumstances has long been documented, leading us to suspect that Xist RNA may have targets and functions beyond the Xi. Here, using female mouse embryonic stem cells (ES) and mouse embryonic fibroblasts (MEF) as a model, we demonstrate that Xist RNA indeed can spread beyond the Xi. However, its binding is limited to ~100 genes in differentiating ES and MEF cells. The target genes are diverse in function but are unified by their active chromatin status. Although active, Xist binding is associated with a downregulation of gene expression. Unlike on the Xi, Xist binding does not lead to full silencing and also does not spread beyond the target gene. Deleting Xist’s Repeat B (RepB) domain reduces Xist’s diffusion away from the Xi and inhibits Xist’s localization to autosomal targets. Nonetheless, Xist transcript lacking RepB fails to down-modulate autosomal gene expression. Altogether, our findings reveal Xist targets beyond the Xi and identify Repeat B as a crucial domain for its in-trans function.

2024-08-23 | GSE271096 | GEO

High-resolution chromosomal maps of Xist RNA reveal a two-step spreading mechanism during X-inactivation

Project description:The Xist long noncoding RNA (lncRNA) is essential for X-chromosome inactivation (XCI), the process by which mammals compensate for unequal numbers of sex chromosomes. During XCI, Xist coats the future inactive X (Xi) and recruits Polycomb Repressive Complex 2 (PRC2) to the X-inactivation center (Xic). Currently unclear is how Xist spreads silencing on a 150 Mb scale. Here we generate high-resolution maps of Xist binding across a developmental time course using CHART-seq. In female cells undergoing XCI de novo, Xist follows a two-step mechanism in which it initially targets gene-rich islands before spreading to intervening gene-poor domains. Xist is depleted from genes that escape XCI but frequently concentrates near escapee boundaries. Xist binding was linearly proportional to PRC2 density and H3 lysine 27 trimethylation (H3K27me3), suggesting co-migration of Xist and PRC2. Interestingly, when the Xi is acutely stripped of Xist in post-XCI cells, Xist recovers quickly within both gene-rich and -poor domains on a time scale of hours instead of days, suggesting a previously primed Xi chromatin state. We conclude that Xist spreading takes on distinct stage-specific forms: During initial establishment, Xist follows a two-step mechanism, but during maintenance, Xist spreads rapidly to both gene-rich and -poor regions. Capture hybridization analysis of RNA targets (CHART) and input samples of (differentiating) mouse embryonic stem (ES) cells and immortalized mouse embryonic fibroblasts (MEF) using paired-end 75 nt reads on Illumina HiSeq2500, with 2 replicates per sample (# of samples). RNA-seq of the same cell lines with 50 nt reads on Illumina HiSeq2000, with 2 replicates per sample (2 samples, 4 datasets total). CHIP-seq: Data from GSE36905 was aligned and processed as CHART-seq samples. Resulting coverage tracks (EZH2/K27me3) are linked directly to GSE48649 (bedGraphs linked below).

2013-11-04 | E-GEOD-48649 | biostudies-arrayexpress

XIST directly regulates X-linked and autosomal genes in naïve human pluripotent cells

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XIST directly regulates X-linked and autosomal genes in naïve human pluripotent cells [RAP-seq_mouse]

2023-12-15 | GSE241440 | GEO

XIST directly regulates X-linked and autosomal genes in naïve human pluripotent cells [RAP-seq_human]

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XIST directly regulates X-linked and autosomal genes in naïve human pluripotent cells [scRNA-seq]

2023-12-15 | GSE241441 | GEO

XIST directly regulates X-linked and autosomal genes in naïve human pluripotent cells [CUT&Tag]

Project description:X-chromosome inactivation (XCI) serves as a paradigm for RNA-mediated regulation of gene expression, wherein the long non-coding RNA XIST spreads across the X-chromosome in cis to mediate chromosome-wide gene silencing. In female naïve human pluripotent stem cells (hPSCs), XIST is in a dispersed configuration and XCI does not occur, raising questions about XIST’s function. We found that XIST spreads across the X-chromosome and induces dampening of X-linked gene expression in naïve hPSCs. Surprisingly, XIST also targets specific autosomal regions, where it induces repressive chromatin changes and gene expression dampening. Thereby, XIST equalizes X-linked gene dosage between male and female cells while inducing differences on autosomes. The dispersed Xist configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. Together, our study identifies XIST as the regulator of X-chromosome dampening, uncovers an evolutionarily conserved trans-acting role of XIST/Xist, and reveals a correlation between XIST/Xist dispersal and autosomal targeting. Surprisingly, XIST also targets specific autosomal regions, where it induces repressive chromatin changes and gene expression dampening. Thereby, XIST equalizes X-linked gene dosage between male and female cells while inducing differences on autosomes. Dispersed Xist configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. Together, our results identify XIST as the regulator of X-chromosome dampening, uncover an evolutionarily conserved trans-acting role of XIST/Xist, and reveal a correlation between XIST/Xist dispersal and autosomal targeting.

2023-12-15 | GSE241443 | GEO

XIST directly regulates X-linked and autosomal genes in naïve human pluripotent cells [ChIP-seq]

2023-12-15 | GSE241442 | GEO

XIST directly regulates X-linked and autosomal genes in naïve human pluripotent cells [RNA-seq]

2023-12-15 | GSE241438 | GEO

Xist Deletional Analysis Reveals an Interdependency between Xist RNA and Polycomb Complexes for Spreading along the Inactive X

Project description:During X-inactivation, Xist RNA spreads along an entire chromosome to establish silencing. However, the mechanism and functional RNA elements involved in spreading remain undefined. By performing a comprehensive endogenous Xist deletion screen, we identify Repeat B as crucial for spreading Xist and maintaining Polycomb repressive complexes 1 and 2 (PRC1/PRC2) along the inactive X (Xi). Unexpectedly, spreading of these three factors is inextricably linked. Deleting Repeat B or its direct binding partner, HNRNPK, compromises recruitment of PRC1 and PRC2. In turn, ablating PRC1 or PRC2 impairs Xist spreading. Therefore, Xist and Polycomb complexes require each other to propagate along the Xi, suggesting a positive feedback mechanism between RNA initiator and protein effectors. Perturbing Xist/Polycomb spreading causes failure of de novo Xi silencing, with partial compensatory downregulation of the active X, and also disrupts topological Xi reconfiguration. Thus, Repeat B is a multifunctional element that integrates interdependent Xist/ Polycomb spreading, silencing, and changes in chromosome architecture.

2019-03-01 | GSE107217 | GEO

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