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Spatio-temporal X-linked gene reactivation in the mouse germline reveals site-specific retention of epigenetic silencing [RNA-seq]

ABSTRACT: Random X-chromosome inactivation (XCI) is a hallmark of female mammalian somatic cells. This epigenetic mechanism, mediated by the long non-coding RNA Xist, occurs in the epiblast and is stably maintained to ensure proper dosage compensation of X-linked genes during life. However, this silencing is lost during primordial germ cell (PGC) development. Using a combination of single-cell allele-specific RNA sequencing and low-input chromatin profiling on in vivo developing mouse PGC, we provide unprecedented detailed maps of gene reactivation. We demonstrate that PGC still carry a fully silent X chromosome at embryonic day (E) 9.5, despite the loss of Xist expression. X-linked genes are then gradually reactivated outside the Xist first-bound regions. At E12.5, a significant part of the inactive X chromosome (Xi) still resists reactivation, carrying an epigenetic memory of its silencing. Late-reactivated genes are enriched in repressive chromatin marks, including DNA methylation and H3K27me3 marks. Our results define the timing of reactivation of the silent X chromosome a key event in female PGC reprogramming with direct implications for reproduction.

ORGANISM(S): Mus musculus

PROVIDER: GSE243942 | GEO | 2025/01/06

REPOSITORIES: GEO

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Spatio-temporal X-linked gene reactivation in the mouse germline reveals site-specific retention of epigenetic silencing [WGBS]

Project description:Random X-chromosome inactivation (XCI) is a hallmark of female mammalian somatic cells. This epigenetic mechanism, mediated by the long non-coding RNA Xist, occurs in the epiblast and is stably maintained to ensure proper dosage compensation of X-linked genes during life. However, this silencing is lost during primordial germ cell (PGC) development. Using a combination of single-cell allele-specific RNA sequencing and low-input chromatin profiling on in vivo developing mouse PGC, we provide unprecedented detailed maps of gene reactivation. We demonstrate that PGC still carry a fully silent X chromosome at embryonic day (E) 9.5, despite the loss of Xist expression. X-linked genes are then gradually reactivated outside the Xist first-bound regions. At E12.5, a significant part of the inactive X chromosome (Xi) still resists reactivation, carrying an epigenetic memory of its silencing. Late-reactivated genes are enriched in repressive chromatin marks, including DNA methylation and H3K27me3 marks. Our results define the timing of reactivation of the silent X chromosome a key event in female PGC reprogramming with direct implications for reproduction.

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Project description:Rett Syndrome is a neurodevelopmental disorder in girls that is caused by heterozygous inactivation of the chromatin remodeler gene MECP2. Rett Syndrome may therefore be treated by reactivation of the wild type copy of MECP2 from the inactive X chromosome. Most studies that model Mecp2 reactivation have used mouse fibroblasts rather than neural cells, which would be critical for phenotypic reversal, and rely on fluorescent reporters that lack adequate sensitivity. Here, we present a mouse model system for monitoring Mecp2 reactivation that is more sensitive and versatile than any bioluminescent and fluorescent system currently available. The model consists of neural stem cells derived from female mice with a dual reporter system where MECP2 is fused to NanoLuciferase and TdTomato on the inactive X chromosome. We show by bioluminescence and fluorescence that Mecp2 is synergistically reactivated by 5-Aza treatment and Xist knockdown. As expected, other genes on the inactive X chromosome are also reactivated, the majority of which overlaps with genes reactivated early during reprogramming of mouse embryonic fibroblasts to iPSCs. Genetic and epigenetic features such as CpG density, SINE elements, distance to escapees and CTCF binding are consistent indicators of reactivation, whereas different higher order chromatin areas are either particularly prone or resistant to reactivation. Our MeCP2 reactivation monitoring system thereby suggests that genetic and epigenetic features on the inactive X chromosome affect reactivation of its genes, irrespective of cell type or procedure of reactivation.

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Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells (RNA-seq)

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Project description:During X-inactivation (XCI), Xist RNA establishes silencing by coating the chromosome in cis and binding diverse proteins to promote formation of a heterochromatic domain. However, Xist repeat B role beyond initiation of XCI remains unclear. Here, we ﬁnd that loss of Xist repeat B in female mice allows survival and leads to a small body size persisting throughout life. Epigenetic and transcriptomic analyses reveal low levels of H3K27me3 and H2AK119ub occupancy on the X chromosome, except in certain CpG island regions, and partial reactivation of X-linked genes on the inactive X across multiple tissues. Notably, overdosage of Usp9x promotes centrosome ampliﬁcation and chromosome instability, increasing the propensity of tumorigenesis. We further demonstrate that Usp9x overdosage leads to abnormalities in asymmetric cell division, thereby affecting the process of cell differentiation. Thus, Xist repeat B is necessary for gene-speciﬁc silencing during XCI maintenance and impacts cell proliferation and differentiation during development. This provides insights into repeat B importance in maintaining XCI.

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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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X Chromosome Reactivation Dynamics Reveal Stages of Reprogramming to Pluripotency

Project description:Reprogramming to iPSCs resets the epigenome of somatic cells including the reversal of X chromosome-inactivation. We sought to gain insight into the steps underlying the reprogramming process by examining the means by which reprogramming leads to X chromosome-reactivation (XCR). Analyzing single cells in situ, we found that hallmarks of the inactive X (Xi) change sequentially, providing a direct readout of reprogramming progression. Several epigenetic changes on the Xi occur in the inverse order of developmental X-inactivation, while others are uncoupled from this sequence. Among the latter, DNA methylation has an extraordinary long persistence on the Xi during reprogramming, and, like Xist expression, is erased only after pluripotency genes are activated. Mechanistically, XCR requires both DNA demethylation and Xist silencing, ensuring that only cells undergoing faithful reprogramming initiate XCR. Our study defines the epigenetic state of multiple sequential reprogramming intermediates and establishes a paradigm for studying cell fate transitions during reprogramming. RRBS profiles were generated from female and male ES cells, female iPS cells, SSEA1+ and SSEA1- reprogramming intermediates, and male and female MEFs, for a total of 18 samples.

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Single cell expression data from ICM cells of mouse blastocysts

Project description:Transcriptional reactivation of the paternal X chromosome occurs in specific cells of the mouse blastocyst between E(mbryonic day)3.5 and E4.5 during pre- to peri-implantation development. While the trophectoderm (TE) and the primitive endoderm (PE) maintain Xist RNA expression and thereby imprinted silencing of genes on the Xp, the epiblast (EPI) cells within the inner cell mass (ICM) gradually downregulate Xist and undergo XCR. To identify differentially expressed genes with potential roles in the XCR process, we performed single-cell expression profiling of ICM cells of blastocysts prior (E3.5, EPI Xist+), during (E4.25, EPI Xist+/Xist-) and after (E4.5, EPI Xist-) XCR. Single cell cDNAs were then assigned to cell-type of origin using qPCR for lineage-specific marker genes (epiblast: Nanog+, PE: Gata6+, TE: Cdx2+). Cells were considered of male sex if they expressed the male marker Eif2s3y or female sex in absence of Eif2s3y and presence of Xist expression in PE cells of the same embryo. Furthermore, female E4.5 epiblast cDNAs were classified according to Xist expression as before (Xist+) or after (Xist-) downregulation during XCR.

2022-11-13 | GSE208430 | GEO

ChIPseq on H4K20me1 on TX1072 cell line at different times of Xist induction through Doxycycline.

Project description:During X chromosome inactivation (XCI), in female mammals, gene silencing is initiated by a long-noncoding RNA, called Xist. Xist RNA accumulation also allows for the deposition of specific chromatin marks. Among others, PRC2-dependent H3K27me3 and PrSet7-dependent H4K20me1 become enriched at the inactive X chromosome. However, the dynamics of this process in relation to Xist RNA accumulation remains unknown as is the molecular mechanism allowing for H4K20me1 enrichment. To follow XCI dynamics in living cells, we developed a genetically encoded, H3K27me3-specific intracellular antibody, or H3K27me3-mintbody. By combining it with live-imaging of H4K20me1, the X chromosome and Xist RNA we uncover striking similarities in the accumulation dynamics of H3K27me3 and H4K20me1. Further ChIP-seq analysis confirmed concurrent accumulation of H4K20me1 and H3K27me3 during XCI albeit with distinct genomic distributions. Xist B and C repeat mutant, which can silence the X but does not allow for H3K27me3 enrichment, also showed lack of H4K20me1 deposition. Thus, both H3K27me3 and H4K20me1 are deposited at the inactive X through a common molecular mechanism but are dispensable for the initiation of gene silencing.

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