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Replication dynamics identifies the folding principles of the inactive X chromosome [RNA-seq]

ABSTRACT: Chromosome-wide late replication is an enigmatic hallmark of the inactive X chromosome (Xi). How it is established and what it represents remains obscure. By single-cell DNA replication sequencing, here we show that the entire Xi is reorganized to replicate rapidly and uniformly in late S-phase upon X-chromosome inactivation (XCI), reflecting its relatively uniform structure revealed by 4C-seq. Despite this uniformity, only a subset of the Xi became earlier replicating in SmcHD1-mutant cells. In the mutant, these domains protruded out of the Xi core, contacted each other, and became transcriptionally reactivated. 4C-seq suggested that they constituted the outermost layer of the Xi even before XCI and were rich in escape genes. We propose that this default positioning forms the basis for their inherent heterochromatin instability in cells lacking the Xi-binding protein SmcHD1 or exhibiting XCI escape. These observations underscore the importance of 3D genome organization on heterochromatin stability and gene regulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE211571 | GEO | 2023/07/11

REPOSITORIES: GEO

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Replication dynamics identifies the folding principles of the inactive X chromosome [4C]

Project description:Chromosome-wide late replication is an enigmatic hallmark of the inactive X chromosome (Xi). How it is established and what it represents remains obscure. By single-cell DNA replication sequencing, here we show that the entire Xi is reorganized to replicate rapidly and uniformly in late S-phase upon X-chromosome inactivation (XCI), reflecting its relatively uniform structure revealed by 4C-seq. Despite this uniformity, only a subset of the Xi became earlier replicating in SmcHD1-mutant cells. In the mutant, these domains protruded out of the Xi core, contacted each other, and became transcriptionally reactivated. 4C-seq suggested that they constituted the outermost layer of the Xi even before XCI and were rich in escape genes. We propose that this default positioning forms the basis for their inherent heterochromatin instability in cells lacking the Xi-binding protein SmcHD1 or exhibiting XCI escape. These observations underscore the importance of 3D genome organization on heterochromatin stability and gene regulation.

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Project description:To investigate the effect of Smchd1 ablation on de novo X chromosome inactivation (XCI), we derived clonal neural progenitor cells (NPCs) from Smchd1+/+ (wild-type, WT) and Smchd1-/- mouse embryonic stem cells (ES cells; ESC). We generated allele-specific RNA-seq datasets from WT and Smchd1-/- NPCs to examine the effect of Smchd1 ablation on gene silencing. In addition, we produced allele-specific ChIP-seq profiles of H3K4me3, H3K27me3, CTCF, and RAD21 and Xist CHART-seq profiles in WT and Smchd1-/- NPCs to investigate the role of SMCHD1 on the distribution of euchromatin, facultative heterochromatin, architectural proteins, and Xist RNA on the inactive X chromosome (Xi). To determine the localization of SMCHD1 on the Xi, we employed allele-specific DamID-seq to map SMCHD1-binding regions in female mouse embryonic fibroblasts. Furthermore, we performed in situ Hi-C on WT NPCs, Smchd1-/- NPCs, and female ES cells undergoing XCI, in order to explore the role of SMCHD1 in regulating the higher-order structure of the Xi.

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Project description:X chromosome inactivation (XCI) silences most genes on one X chromosome in female mammals, but some genes escape XCI. To identify escape gene in vivo and to explore molecular mechanisms that regulate this process we analyzed the allele-specific expression and chromatin structure of X-linked genes in mouse tissues and cells with skewed XCI and distinguishable alleles based on single nucleotide polymorphisms. Using a new method to estimate allelic expression, we demonstrate a continuum between complete silencing and significant expression from the inactive X (Xi). Few genes (2-3%) escape XCI to a significant level and only a minority differs between mouse tissues, suggesting stringent silencing and escape controls. Allelic profiles of DNase I hypersensitivity and RNA polymerase II occupancy of genes on the Xi correlate with escape from XCI. Allelic binding profiles of the DNA binding protein CCCTC-binding factor (CTCF) in different cell types indicate that CTCF binding at the promoter correlates with escape. Importantly, CTCF binding at the boundary between escape and silenced domains may prevent the spreading of active escape chromatin into silenced domains. Examination of allelic expression in mouse hybrid tissues.

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Unfolding the inactive X chromosome

Project description:The inactive X chromosome (Xi) is folded in a stepwise process into a compartment-less structure. Here we investigate if the Xi can be unfolded in post-XCI cells. We began with ablating structural maintenance of chromosomes hinge domain containing 1 (Smchd1) in female mouse embryonic fibroblasts (MEFs), a cell type in which XCI is completed. We then performed in situ Hi-C on one Smchd1+/+ (wild-type, WT) and one Smchd1-/- (knockout, KO) MEF clone to probe the role of SMCHD1 in maintaining the higher-order structure of the Xi. To determine if the change in chromosome structure is accompanied by altered gene expression, we performed RNA-seq on two WT and two independently generated Smchd1-/- clones treated with either DMSO or 5-aza-2'-deoxycytidine (Aza), a DNA demethylating agent. In addition, we performed H3K27me3 and H2AK119ub ChIP-seq and Xist Capture Hybridization Analysis of RNA Targets with deep sequencing (CHART-seq) on one WT and one Smchd1-/- MEF clone to determine if there is an alteration in the epigenetic state of the Smchd1-/- Xi. Finally, we examined the role of Xist, Polycomb repressive complex 1 (PRC1), and Heterogeneous Nuclear Ribonucleoprotein K (HNRNPK) in regulating the Xi structure in post-XCI cells. To do so we performed in situ Hi-C on WT and Smchd1-/- MEFs depleted with either PRC1 or HNRNPK, as well as on fibroblasts in which Xist is deleted on the Xi (XidelXist).

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Project description:X-chromosome inactivation (XCI) entails a massive structural reorganization of the inactive X (Xi). However the molecular architecture of the Xi is unknown. Here we show that the Xi lacks typical autosomal features such as active/inactive compartments and topologically associating domains (TADs), except around a small number of genes that escape XCI and remain expressed. Escaping genes form TADs and retain DNA accessibility at promoter-proximal and CTCF binding sites, indicating that these loci can avoid Xist-mediated erasure of chromosomal structure. We further show that genesilencing competent Xist RNA is sufficient to induce segregation of the Xi into two ‘mega-domains’ separated by a boundary that includes the DXZ4 macrosatellite. Deletion of this boundary prior to XCI results in fusion of the megadomains and altered patterns of escape that correlate with changes in TAD structure following differentiation and XCI . Our results suggest a critical role for the boundary locus and Xist RNA in shaping the structure of the Xi and modulating escape from XCI. Our findings also point to roles of transcription and CTCF binding in TAD formation in the context of facultative heterochromatin.

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Project description:The spatial proximity between regulatory elements and their target genes has a profound affect on gene expression. X Chromosome Inactivation (XCI) is an epigenetic process by which an entire chromosome is rendered, for the most part, transcriptionally silent. A few genes are known to escape XCI and the mechanism for this escape remains unclear. Here, using mouse trophectodermal stem cells, we address whether specific chromosomal interactions facilitate escape from XCI by bringing escape-specific regulatory elements in close proximity to gene promoters. Our results suggest a model where escape from XCI occurs within topologically associated domains. As such, escaping genes and the regulatory sequences required for their escape are likely located within close linear proximity to each other. The datasets provided include those generated from allele-specific 4C-Seq of genes escaping XCI, genes subject to XCI, and non-genic regions of the X chromosome. FASTQ files, text files containing genomic coordiantes, and BED aligmnets are provided. All sequences were mapped relative to mouse genome build mm9. Deep sequencing of circular chromosome conformation capture (4C-Seq) of genes escaping X inactivation in mouse trophoblast stem cells

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