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Xist exerts gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis [RNA-seq]

ABSTRACT: X chromosome inactivation (XCI) is a dosage compensation phenomenon that occurs in females. Initiation of XCI depends on Xist RNA, which triggers silencing of one of the two X chromosomes, except for XCI escape genes that continue to be biallelically expressed. In the soma XCI is stably maintained with continuous Xist expression. How Xist impacts XCI maintenance remains an open question. Here we conditionally deleted Xist in hematopoietic system of mice and report differentiation and cell cycle defects in female hematopoietic stem and progenitor cells (HPSCs). By utilizing female HSPCs and mouse embryonic fibroblasts, we find that X-linked genes show variable tolerance to Xist loss. Specifically, XCI escape genes exhibit preferential transcriptional upregulation, which associates with low H3K27me3 occupancy, and high chromatin accessibility that accommodates preexisting binding of transcription factors such as Yin Yang 1 (YY1) at the basal state. We conclude that Xist is necessary for gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE184772 | GEO | 2022/07/15

REPOSITORIES: GEO

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Xist exerts gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis [ATAC-seq]

Project description:X chromosome inactivation (XCI) is a dosage compensation phenomenon that occurs in females. Initiation of XCI depends on Xist RNA, which triggers silencing of one of the two X chromosomes, except for XCI escape genes that continue to be biallelically expressed. In the soma XCI is stably maintained with continuous Xist expression. How Xist impacts XCI maintenance remains an open question. Here we conditionally deleted Xist in hematopoietic system of mice and report differentiation and cell cycle defects in female hematopoietic stem and progenitor cells (HPSCs). By utilizing female HSPCs and mouse embryonic fibroblasts, we find that X-linked genes show variable tolerance to Xist loss. Specifically, XCI escape genes exhibit preferential transcriptional upregulation, which associates with low H3K27me3 occupancy, and high chromatin accessibility that accommodates preexisting binding of transcription factors such as Yin Yang 1 (YY1) at the basal state. We conclude that Xist is necessary for gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis.

2022-07-15 | GSE184770 | GEO

Xist exerts gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis [RNA-seq MEFs]

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Xist exerts gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis [ChIP-seq MEFs]

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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

SPEN is a molecular integrator that bridges Xist with transcriptional and epigenetic control of X-chromosome inactivation

Project description:Xist represents a paradigm for long non-coding RNA function in epigenetic regulation, although how it mediates X-chromosome inactivation (XCI) remains largely unexplained. Multiple Xist-RNA binding proteins have recently been identified, including SPEN/SHARP, whose knockdown has been associated with deficient XCI at multiple loci. Here we demonstrate that SPEN is a key orchestrator of XCI in vivo and unravel its mechanism of action. We show that SPEN is essential for initiating gene silencing on the X chromosome in preimplantation mouse embryos and embryonic stem cells. On the other hand, SPEN is dispensable for maintenance of XCI in neural progenitor cells, although it significantly dampens expression of genes that escape from XCI. During initiation of XCI, we show by live-cell imaging and CUT&RUN approaches that SPEN is immediately recruited to the X chromosome upon Xist up-regulation, where it is targeted to enhancers and promoters of actively transcribed genes. SPEN rapidly disengages from chromatin once silencing is accomplished, implying a need for active transcription to tether it to chromatin. We define SPEN’s SPOC (SPEN paralog and ortholog C-terminal) domain as a major effector of SPEN’s gene silencing function, and show that artificial tethering of SPOC to Xist RNA is sufficient to mediate X-linked gene silencing. We identify SPOC’s protein partners which include NCOR/SMRT, the m6A RNA methylation machinery, the NuRD complex, RNA polymerase II and factors involved in regulation of transcription initiation and elongation. We propose that SPEN acts as a molecular integrator for initiation of XCI, bridging Xist RNA with the transcription machinery as well as nucleosome remodelers and histone deacetylases, at active enhancers and promoters.

2021-04-19 | PXD015699 | Pride

The efficiency of Xist-mediated silencing of X-linked and autosomal genes is determined by the genomic environment

Project description:Xist is indispensable for X chromosome inactivation (XCI) in female mammalian cells. However, how Xist RNA directs chromosome-wide transcriptional inactivation of the X chromosome is largely unknown. Here, to study chromosome inactivation by Xist, we generated a system where ectopic Xist expression can be induced from several genomic contexts in aneuploid mouse ES cells. We found that ectopic Xist expression from any location on the X chromosome faithfully recapitulated endogenous XCI, showing the potency of Xist to initiate XCI. Genes that escape XCI remain consistently transcriptionally active upon ectopic XCI, regardless of their position relative to Xist transgenes, and the enrichment of CTCF at their promoters is implicated in directing XCI escape. Xist expression from autosomes facilitates their transcriptional silencing to different degrees, and gene density in proximity of the Xist transcription locus plays a central role in determining the efficiency of gene inactivation. We also show that the enrichment of LINE elements together with a specific chromatin environment facilitates Xist-mediated silencing of both X-linked and autosomal genes. These findings provide new insights into the epigenetic mechanisms that mediate XCI and identify genomic features that promote Xist-mediated chromosome-wide gene inactivation

2017-07-04 | GSE92894 | GEO

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

2013-11-04 | GSE48649 | GEO

Rlim-independent XCI in female embryonic stem cells in vitro

Project description:The transcriptomes of differentiated and undifferentiated E14 (male), Pgk12.1 (female; WT) and Pgk12.1 with a KO of Rlim (RlimKO) were elucidated and examined for differences in X chromosome inactivation. No significant differences between wt and RlimKO with respect to Xist expression and global X-silencing was detected. Results confirm that Rlim is not required for XCI in female ESCs.

2017-12-26 | GSE101838 | GEO

Allele-specific ATAC-seq over a timecourse of inducible XCI in mESCs

Project description:X chromosome inactivation (XCI) in mammals is mediated by Xist RNA which functions in cis to silence genes on a single X chromosome in XX female cells, thereby equalising levels of X-linked gene expression relative to XY males. XCI progresses over a period of several days, with some X-linked genes silencing faster than others. Chromosomal location of a gene is an important determinant of silencing rate, but uncharacterised gene-intrinsic features also mediate resistance or susceptibility to silencing. In this study, we examine mouse embryonic stem cell lines with an inducible Xist allele (iXist-ChrX mESCs) and integrate allele-specific data of gene silencing and decreasing inactive X (Xi) chromatin accessibility over time-courses of Xist induction with cellular differentiation. Our analysis reveals that motifs bound by the transcription factor YY1 are associated with persistently accessible regulatory elements, including many promoters and enhancers of slow-silencing genes. We further show that YY1 is evicted relatively slowly from target sites on Xi, and that silencing of X-linked genes is increased upon YY1 degradation. Together our results suggest that YY1 acts as barrier to Xist-mediated silencing until late stages of the XCI process.

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