Resolving the 4D chromatin dynamics during early random X chromosome inactivation II
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE310759 | GEO | 2026/01/01
REPOSITORIES: GEO
Similar Datasets
Project description:X chromosome inactivation (XCI) is a process that compensates X-linked gene dosage in mammalian female cells. The silencing of a randomly selected chromosome is accompanied by dramatic three-dimensional (3D) reorganization across the entire chromosome. To investigate the 4D chromatin dynamics during early inactivation stages, we applied the multi-omics sequencing technique HiRES, which simultaneously detects 3D genome and transcriptome in single cells, in a mouse embryonic stem cell line with induced random XCI. The 3D genome and transcriptome dual-omics data allowed us to identify XCI lineages at single-cell resolution. We characterized multiple layers of chromosome reorganization during random XCI and discovered a transient structural inactivation state for both X chromosomes resulted from biallelic Xist expression. By constructing single-cell inactivation trajectories, we found that a vast majority of chromatin remodeling either accompanied or followed gene silencing. Further analysis of interaction decay kinetics revealed that TAD attenuation began from loss of interactions on TAD anchors. This study thus drew a detailed depiction of fine-scale chromatin reorganization during the initiation of random XCI.
2025-09-26 | GSE278310 | GEO
Project description:Three-dimensional chromatin structures undergo dynamic reorganization during mammalian spermatogenesis; however, their impacts on gene regulation remain unclear. Here, we focused on understanding the structure-function regulation of meiotic chromosomes by Hi-C and other omics techniques in mouse spermatogenesis across five sequential stages. Beyond confirming recent reports regarding changes in compartmentalization and reorganization of topologically associating domains (TADs), we further demonstrated that chromatin loops are present prior to and after, but not at, the pachytene stage. By integrating Hi-C and RNA-Seq data, we showed that the switching of A/B compartments between spermatogenic stages is tightly associated with meiosis-specific mRNAs and piRNAs expression. Moreover, our ATAC-Seq data indicated that chromatin accessibility per se is not responsible for the TAD and loop diminishment at pachytene. Additionally, our ChIP-Seq data demonstrated that CTCF and cohesin remain bound at TAD boundary regions throughout meiosis, suggesting that dynamic reorganization of TADs does not require CTCF and cohesin clearance.
2020-03-26 | GSE147536 | GEO
Project description:One of the two X chromosomes in female somatic cells is transcriptionally silenced across cell generations, a classic paradigm of epigenetic regulation. Although most genes are stably silenced, certain X-linked genes escape X-chromosome inactivation (XCI), providing a fundamental dosage difference between females and males. A role for chromosome conformation has been proposed in XCI as the process is accompanied by a massive structural reorganisation. However a detailed molecular understanding of the three-dimensional architecture of the Xi has been lacking. Here we reveal an unusual three-dimensional configuration of the Xi, that provides novel insights into the relationship between gene expression and TAD organisation. Using allele-specific Hi-C, RNA-Seq and ATAC-seq, as well as DNA FISH, we show that the Xi is spatially segregated into two ‘mega-domains’ separated by a 200kb boundary including the DXZ4 macrosatellite, and is globally devoid of typical autosomal structural features such as active/inactive compartments and topologically associating domains (TADs). However, we find that a few regions along the Xi display TAD signatures corresponding to regions containing escape genes, and display DNA accessibility at promoter-proximal TF binding sites. Strikingly, when the DXZ4-containing boundary region is deleted prior to XCI, most facultative escapees are no longer expressed from the Xi, and the escape associated chromatin domains are no longer observed. Deletion of the DXZ4-containing boundary region from the Xi also results in fusion of the two mega-domains. We show that Xist A-repeat containing (gene silencing competent) RNA is sufficient to induce this spatial segregation of the X chromosome. Combined, our results point to a critical role for the DXZ4-boundary region, together with Xist RNA, in shaping the higher order structure of the Xi and in allowing facultative escape from XCI during differentiation. They also point to direct and uncover a close relationships between transcription and TAD formation organisation in the context of the Xi.
2016-06-30 | GSE71156 | GEO
Project description:Doxorubicin resistance remains a major therapeutic challenge leading to treatment failure and poor survival prognosis in breast cancer. Although doxorubicin induces massive changes in the transcriptional landscape accompanied by alterations of chromatin accessibility are well known, potential diagnostic or therapeutic targets associated with three-dimensional (3D) genome reorganization in doxorubicin-resistant breast cancer cells have not yet been systematically investigated. Here we performed integrated analyses combining in situ high-throughput chromosome conformation capture (Hi-C), ATAC-seq and mHi-C data on doxorubicin-resistant MCF7 human breast cancer cells compared to parental cells. It revealed that A/B compartment switching was positively correlated to genome-wide differential gene expression, and the genome was spatially reorganized into smaller topologically associating domains (TADs) and loops. We also revealed the contribution of increased chromatin accessibility and potential transcription factor families, including CTCF and BORIS, to gained TAD boundaries and loop anchors. Intriguingly, we observed two condensed genomic regions (~20kb) with decreased chromatin accessibility flanking TAD boundaries, which might play a critical role in the formation or maintenance of TADs. Moreover, we identified a number of gained and lost enhancer-promoter interactions associated with differentially expressed genes, including FA2H, FOXA1, JRKL and EZH, some of which involved in chromatin organization and breast cancer signaling pathways. This study uncovered a close connection between 3D genome reorganization, chromatin accessibility as well as gene transcription, and provides resources and novel insights into the epigenomic mechanisms with potential therapeutic implications for doxorubicin resistance in breast cancer.
2022-06-14 | GSE205874 | GEO
Project description:Topologically associating domains (TADs) are thought to restrict the action of distal cis-regulatory elements, such as enhancers, to target gene promoters within the same TAD. Here we discover that a cis-regulatory element of Xist is located almost 200kb away from its promoter and across a TAD boundary. This element, the promoter of a noncoding RNA, Linx, opposes Xist up-regulation in cis and influences the choice of X chromosome to be inactivated. Even though Linx lies in the same TAD as Xist’s antisense Tsix locus, we show that the repressive action of Linx on Xist is independent of Tsix. Furthermore, this Xist regulatory action is independent of Linx transcript or of its transcription. Finally, we demonstrate that Linx cis-regulatory repressive element is well conserved in mammals, unlike Tsix, suggesting that it represents an ancestral mechanism for random monoallelic Xist expression. Our study uncovers a novel regulatory axis for X-chromosome inactivation and a new class of cis-regulatory effects that rely on TAD partitioning to modulate developmental decisions.
2019-12-01 | GSE124596 | GEO
Project description:The spatial arrangement of interphase chromosomes in the nucleus is important for gene expression and genome function in animals and in plants. The recently developed Hi-C technology is an efficacious method to investigate genome packing. Here we present a detailed Hi-C map of the three-dimensional genome organization of the plant Arabidopsis thaliana. We find that local chromatin packing differs from the patterns seen in animals, with kilobasepair-sized segments that have much higher intra-chromosome interaction rates than neighboring regions and which represent a dominant local structural feature of genome conformation in A. thaliana. These regions appear as positive strips on two-dimensional representations of chromatin interaction and they are enriched in epigenetic marks H3K27me3, H3.1 and H3.3. We also identify over 400 insulator-like regions. Furthermore, although topologically associating domains (TADs), which are prominent in animals, are not the dominant feature of A. thaliana genome packing, we found over 1,000 regions that have properties of TAD boundaries, and a similar number of regions similar to the interior of TADs. These insulator-like, TAD-boundary-like, and TAD-interior-like regions show strong enrichment for distinct epigenetic marks, and correlate with gene transcription levels. We conclude that epigenetic modifications, gene density, and transcriptional activity all contribute to shaping the local structure of the A. thaliana nuclear genome.
2014-09-24 | E-MTAB-4438 | biostudies-arrayexpress
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a devastating premature aging disorder driven by the accumulation of progerin, leading to severe vascular pathology. While epigenetic alterations are implicated, the spatiotemporal reorganization of the higher-order chromatin and its functional impact on vascular smooth muscle cell (VSMC) transcription remain poorly defined. Through an integrated multi-omics approach combining in situ high-throughput chromosome conformation capture (Hi-C) and Cleavage Under Targets and Tagmentation (CUT&Tag) profiling of CTCF, SMC1A, H3K27me3, H3K27ac, and H3K36me3 with transcriptomic analyses from control and HGPS iPSC-derived VSMCs, we reveal that global topologically associating domain (TAD) architecture remains largely intact in HGPS. However, the internal chromatin states of TADs undergo dynamic, passage-specific remodeling, characterized by a progressive accumulation of broad H3K27me3-repressed domains. This is accompanied by a loss of A/B compartment segregation, as confirmed by DNA-FISH, indicating a collapse of higher-order chromatin organization in late passage. Crucially, we uncover widespread rewiring of enhancer-promoter (E-P) loops, which is linked to the dysregulation of genes critical for vascular development, extracellular matrix organization, and atherosclerosis. Our study demonstrates that spatiotemporal redistribution of repressive histone marks and reorganization of E-P interactions within a structurally resilient TAD framework underpin widespread transcriptional dysregulation in HGPS vascular pathogenesis. This uncovers a critical dissociation between higher-order chromatin architecture and epigenetic statehistone modification landscape, providing a mechanistic basis for the failure of vascular homeostasis in progeria.
2025-12-04 | GSE312031 | GEO
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a devastating premature aging disorder driven by the accumulation of progerin, leading to severe vascular pathology. While epigenetic alterations are implicated, the spatiotemporal reorganization of the higher-order chromatin and its functional impact on vascular smooth muscle cell (VSMC) transcription remain poorly defined. Through an integrated multi-omics approach combining in situ high-throughput chromosome conformation capture (Hi-C) and Cleavage Under Targets and Tagmentation (CUT&Tag) profiling of CTCF, SMC1A, H3K27me3, H3K27ac, and H3K36me3 with transcriptomic analyses from control and HGPS iPSC-derived VSMCs, we reveal that global topologically associating domain (TAD) architecture remains largely intact in HGPS. However, the internal chromatin states of TADs undergo dynamic, passage-specific remodeling, characterized by a progressive accumulation of broad H3K27me3-repressed domains. This is accompanied by a loss of A/B compartment segregation, as confirmed by DNA-FISH, indicating a collapse of higher-order chromatin organization in late passage. Crucially, we uncover widespread rewiring of enhancer-promoter (E-P) loops, which is linked to the dysregulation of genes critical for vascular development, extracellular matrix organization, and atherosclerosis. Our study demonstrates that spatiotemporal redistribution of repressive histone marks and reorganization of E-P interactions within a structurally resilient TAD framework underpin widespread transcriptional dysregulation in HGPS vascular pathogenesis. This uncovers a critical dissociation between higher-order chromatin architecture and epigenetic statehistone modification landscape, providing a mechanistic basis for the failure of vascular homeostasis in progeria.
2025-12-04 | GSE312029 | GEO
Project description:TAD (Topologically Associating Domain) reorganization occurs commonly in cell nucleus and contributes to gene activation and inhibition through separation or fusion of adjacent TADs. However, identification of functional genes impacted by TAD alteration and revealing of TAD-reorganization mechanism underlying gene transcription remain to be fully elucidated. Here, we firstly developed a novel approach termed Inter3D to specifically dig out genes regulated by TAD reorganization. By constructing the comprehensive TAD reorganization medicating epigenomic landscapes in tumor cells, we showed that TAD separation interrupted the intrachromosomal loop at MYL12B locus and abrogated its transcription, while TAD fusion generated the chromosomal interaction and triggered CYP27B1 activation. Our study provides a comprehensive insight into capture of TAD rearrangement-mediated gene loci and moves towards recognizing the functional role of TAD reorganization in gene transcription.
2024-04-29 | GSE230795 | GEO
Project description:TAD (Topologically Associating Domain) reorganization occurs commonly in cell nucleus and contributes to gene activation and inhibition through separation or fusion of adjacent TADs. However, identification of functional genes impacted by TAD alteration and revealing of TAD-reorganization mechanism underlying gene transcription remain to be fully elucidated. Here, we firstly developed a novel approach termed Inter3D to specifically dig out genes regulated by TAD reorganization. By constructing the comprehensive TAD reorganization medicating epigenomic landscapes in tumor cells, we showed that TAD separation interrupted the intrachromosomal loop at MYL12B locus and abrogated its transcription, while TAD fusion generated the chromosomal interaction and triggered CYP27B1 activation. Our study provides a comprehensive insight into capture of TAD rearrangement-mediated gene loci and moves towards recognizing the functional role of TAD reorganization in gene transcription.
2024-04-29 | GSE230797 | GEO