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NFkB Signaling is Required for Xist RNA Localization at the Inactive X and for X-Chromosome Inactivation Maintenance Following T cell Activation [RNAseq_ESCAPE_stimulation]

ABSTRACT: X Chromosome Inactivation (XCI) is a female-specific process which balances X-linked gene dosage between sexes. Unstimulated T cells lack cytological enrichment of Xist RNA and heterochromatic modifications on the inactive X chromosome (Xi), and these modifications become enriched at the Xi after cell stimulation. Here, we examined allele-specific gene expression and epigenomic profiling of the Xi following T cell stimulation. We found that the Xi in unstimulated T cells is dosage compensated, and is enriched with the repressive H3K27me3 modification, but not H2AK119-ubiquitin (Ub) mark, including at promoters of XCI escape genes. Upon CD3/CD28 mediated T cell stimulation, the Xi accumulates H2AK119-Ub and H3K27me3 across the Xi. Next, we examined the T cell stimulation pathways responsible for Xist RNA localization to the Xi and found that T cell receptor (TCR) engagement, specifically NFkB signaling downstream of TCR, is required. Disruption of NFkB signaling, using inhibitors or genetic deletions, in mice and patients with immunodeficiencies prevents Xist/XIST RNA accumulation at the Xi and alters expression of some X-linked genes. Our findings reveal a novel connection between NFkB signaling pathways which impact XCI maintenance in female T cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE251881 | GEO | 2024/10/29

REPOSITORIES: GEO

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NFkB Signaling is Required for Xist RNA Localization at the Inactive X and for X-Chromosome Inactivation Maintenance Following T cell Activation [RNAseq_geneexpression]

Project description:X Chromosome Inactivation (XCI) is a female-specific process which balances X-linked gene dosage between sexes. Unstimulated T cells lack cytological enrichment of Xist RNA and heterochromatic modifications on the inactive X chromosome (Xi), and these modifications become enriched at the Xi after cell stimulation. Here, we examined allele-specific gene expression and epigenomic profiling of the Xi following T cell stimulation. We found that the Xi in unstimulated T cells is dosage compensated, and is enriched with the repressive H3K27me3 modification, but not H2AK119-ubiquitin (Ub) mark, including at promoters of XCI escape genes. Upon CD3/CD28 mediated T cell stimulation, the Xi accumulates H2AK119-Ub and H3K27me3 across the Xi. Next, we examined the T cell stimulation pathways responsible for Xist RNA localization to the Xi and found that T cell receptor (TCR) engagement, specifically NFkB signaling downstream of TCR, is required. Disruption of NFkB signaling, using inhibitors or genetic deletions, in mice and patients with immunodeficiencies prevents Xist/XIST RNA accumulation at the Xi and alters expression of some X-linked genes. Our findings reveal a novel connection between NFkB signaling pathways which impact XCI maintenance in female T cells.

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RNA-Seq analysis of murine splenic B cells with deletion of YY1

Project description:X chromosome inactivation (XCI) in female lymphocytes is uniquely regulated, as the inactive X (Xi) chromosome lacks localized Xist RNA and heterochromatin modifications. Epigenetic profiling reveals that Xist RNA is lost from the Xi at the pro-B cell stage and that additional heterochromatic modifications are gradually lost during B cell development. Activation of mature B cells restores Xist RNA and heterochromatin to the Xi in a dynamic two-step process that differs in timing and pattern, depending on the method of B cell stimulation. Finally, we find that DNA binding by YY1 maintains XCI in activated B cells, as ex-vivo YY1 deletion results in loss of Xi heterochromatin marks and up-regulation of X-linked genes. Ectopic expression of the YY1 zinc finger domain is sufficient for Xist RNA localization during B cell activation. Together, our results indicate that Xist RNA localization is critical for maintaining XCI in female lymphocytes, and that chromatin changes on the Xi during B cell development and the dynamic nature of YY1-dependent XCI maintenance in mature B cells predisposes X- linked immunity genes to reactivation.

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ChIP-sequencing (ChIP-seq) experiments on female ESCs expressing V5-tagged REX1 and control wild-type Embryonic stem cells (ESCs)

Project description:Evolution of the mammalian sex chromosomes has resulted in a heterologous X and Y pair, where the Y chromosome has lost most of its genes. Hence, there is a need for X-linked gene dosage compensation between XY males and XX females. In placental mammals, this is achieved by random inactivation of one X chromosome (XCI) in all female somatic cells. Up-regulation of Xist transcription on the future inactive X chromosome (Xi) acts against Tsix antisense transcription, and spreading of Xist RNA in cis triggers epigenetic changes leading to XCI. Previously, we have shown that the X-encoded E3 ubiquitin ligase RNF12 is up-regulated in differentiating mouse embryonic stem cells (ESCs) and activates Xist transcription and XCI. Here, we have identified the pluripotency factor REX1 as a key target of RNF12 in the XCI mechanism. RNF12 causes ubiquitination and proteasomal degradation of REX1, and Rnf12 knockout mouse ESCs show an increased level of REX1. Using ChIP-seq, REX1 binding sites were detected in Xist and Tsix regulatory regions. Over-expression of REX1 in female ESCs was found to inhibit Xist transcription and XCI, whereas male Rex1+/- ESCs showed ectopic XCI. From this, we propose that RNF12 causes REX1 breakdown through dose-dependent catalysis, thereby representing an important pathway to initiate XCI. Rex1 and Xist are present only in placental mammals, which points to co-evolution of these two genes and XCI. 2 (one control one pulldown) samples

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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).

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Project description:At initiation of X chromosome inactivation (XCI), Xist is monoallelically upregulated from the future inactive X (Xi) chromosome, overcoming repression by its antisense transcript Tsix. Xist recruits various chromatin remodelers, amongst them SPEN, which are involved in silencing of X-linked genes in cis and establishment of the Xi. Here, we show that SPEN plays an important role in the initiation of XCI. Spen null female mouse embryonic stem cells (ESCs) are defective in Xist upregulation upon differentiation. We find that Xist-mediated SPEN recruitment to the Xi chromosome happens very early in XCI, and that SPEN-mediated silencing of the Tsix promoter is required for Xist upregulation. Accordingly, failed Xist upregulation in Spen-/- ESCs can be rescued by concomitant removal of Tsix. These findings indicate that SPEN is not only required for the establishment of the Xi, but is also crucial in the initiation of the XCI process.

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Copy number variant (CNV) and Single nucleotide polymorphism (SNP) of UCLA hESC lines

Project description:Female human ESC-lines can carry active X-chromosomes (Xa) or an XIST-RNA- coated inactive X-chromosome (Xi XIST+ ). Additionally, many ESC-lines have abnormal X-chromosome-inactivation (XCI)-states where the Xi no longer expresses XIST-RNA and has transcriptionally active regions (eroded Xi=Xe). The fate of each XCI-state upon differentiation is unclear because individual lines often contain a mixture of XCI-states. Here, we established homogeneous XiXa, XeXa, and XaXa ESC-lines. We found that these lines were unable to initiate XIST-expression and X-chromosome- wide silencing upon differentiation indicating that the ESC XCI-state is maintained in differentiated cells. Consequently, differentiated XeXa and XaXa cells displayed higher levels of X-linked gene-expression than XiXa cells. Although global transcriptional compensation between X-chromosomes and autosomes is not required for female ESC-differentiation, the degree of X-chromosome- silencing influences differentiation efficiencies. Our data suggest that the Xi XIST+ Xa state is inherent to human ESCs and that all other XCI-states, including XaXa, are abnormal and arise during ESC-derivation or maintenance.

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