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Non-coding loci without epigenomic signals can be essential for maintaining global chromatin organization and cell viability [HiC]

ABSTRACT: Most non-coding regions of the human genome do not harbour any annotated element and are even not marked with any epigenomic or protein binding signal. However, an overlooked aspect of their possible role in stabilizing 3D chromatin organization has not been extensively studied. To illuminate their structural importance, we started with the non-coding regions forming many 3D contacts (referred to as hubs) and performed a CRISPR library screening to identify dozens of hubs essential for cell viability. Hi-C and single cell transcriptomic analyses showed that their deletion could significantly alter chromatin organization and impact the distal genes expression. This study revealed the 3D structural importance of non-coding loci that are not associated with any functional element, providing a new mechanistic understanding of disease-associated genetic variations (GVs), and we focused on single nucleotide variations. Furthermore, our analyses also suggest a powerful approach to develop "one-drug-multiple-targets" therapeutics targeting disease-specific non-coding regions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE176500 | GEO | 2021/08/25

REPOSITORIES: GEO

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Non-coding loci without epigenomic signals can be essential for maintaining global chromatin organization and cell viability [single-cell RNA-seq]

Project description:Most non-coding regions of the human genome do not harbour any annotated element and are even not marked with any epigenomic or protein binding signal. However, an overlooked aspect of their possible role in stabilizing 3D chromatin organization has not been extensively studied. To illuminate their structural importance, we started with the non-coding regions forming many 3D contacts (referred to as hubs) and performed a CRISPR library screening to identify dozens of hubs essential for cell viability. Hi-C and single cell transcriptomic analyses showed that their deletion could significantly alter chromatin organization and impact the distal genes expression. This study revealed the 3D structural importance of non-coding loci that are not associated with any functional element, providing a new mechanistic understanding of disease-associated genetic variations (GVs), and we focused on single nucleotide variations. Furthermore, our analyses also suggest a powerful approach to develop "one-drug-multiple-targets" therapeutics targeting disease-specific non-coding regions.

2021-08-25 | GSE176502 | GEO

Non-coding loci without epigenomic signals can be essential for maintaining global chromatin organization and cell viability [bulk RNA-seq]

Project description:In this study, we performed network analysis on Hi-C data and identified a group of non-coding regions forming many 3D contacts (referred to as hubs). Through a high-throughput CRISPR-Cas9 library screening by targeted deletion, we discovered that some hubs without any epigenetic marks were essential for cell growth and survival. Hi-C and single cell transcriptomic analyses showed that their deletion could significantly alter chromatin organization and impact the distal genes expression. This study revealed the 3D structural importance of non-coding loci that are not associated with any functional element, providing a new mechanistic understanding of disease-associated genetic variations. Furthermore, our analyses also suggest a powerful approach to develop "one-drug-multiple-targets" therapeutics targeting disease-specific non-coding regions.

2021-08-25 | GSE176501 | GEO

Whole genome analysis of pediatric patients with medulloblastoma

Project description:Cancer genomes often contain structural variations (SVs) in non-coding regions, while its impact on tumorigenesis is still unclear. Our goal is to discover genome folding changes resulted from SVs using InfoGenomeR and InfoHiC frameworks, which may reveal novel therapeutic targets. We applied our frameworks to five pediatric patients with medulloblastoma, revealing 3D genome changes of medulloblastoma driver genes.

| EGAS00001006653 | EGA

Cis-Regulatory Element Hijacking by Structural Variants Overshadows Topological Changes in Primary Prostate Cancer

Project description:Prostate cancer is a heterogeneous disease whose progression is linked to genome instability. However, the impact of this instability on the non-coding genome and its three-dimensional organization to aid progression is unclear. Using primary benign and tumor tissue, we find a high concordance in higher order three-dimensional genome organization. This concordance argues for constraints to the topology of prostate tumor genomes. Nonetheless, we identified changes in focal chromatin interactions, typical of loops bridging non-coding cis-regulatory elements, and showed how structural variants can induce these changes to guide cis-regulatory element hijacking. Such events resulted in opposing differential expression of genes found at antipodes of rearrangements. Collectively, these results argue that changes to focal chromatin interactions, as opposed to higher order genome organization, allow for aberrant gene regulation and are repeatedly mediated by structural variants in primary prostate cancer.

2021-01-07 | GSE164347 | GEO

CEBPA phase separation links transcriptional activity and 3D chromatin hubs

Project description:Cell identity is orchestrated through an interplay between transcription factor (TF) action and genome architecture. The mechanisms used by TFs to shape three-dimensional (3D) genome organization remain incompletely understood. Here we present evidence that the lineage-instructive TF CEBPA drives extensive chromatin compartment switching and promotes the formation of long-range chromatin hubs during induced B cell to macrophage transdifferentiation. A large intrinsically disordered region (IDR) enables CEBPA to undergo in vitro phase separation and to co-condense with transcriptional partners, which is at least partially mediated by aromatic residues. Furthermore, CEBPA forms visible nuclear condensates in transdifferentiating B cells that co-localize with co-activator condensates and recover rapidly upon photobleaching. Finally, native CEBPA-expressing cell types such as primary granulocyte-macrophage progenitors (GMPs), liver cells and trophectoderm cells also reveal nuclear CEBPA condensates and long-range 3D chromatin hubs at CEBPA-bound regions. These findings support a model in which CEBPA acts as a 3D genome structural organizer and suggest that this effect is mediated at least in part by its phase-separation capacity.

2023-07-24 | GSE221167 | GEO

The International Cancer Genome project: Pan-Cancer Analysis of Whole Genomes (PCAWG)

Project description:The Pan-Cancer Analysis of Whole Genomes (PCAWG) study is an international collaboration to identify common patterns of mutation in more than 2,800 cancer whole genomes from the International Cancer Genome Consortium. Building upon previous work which examined cancer coding regions, this project is exploring the nature and consequences of somatic and germline variations in both coding and non-coding regions, with specific emphasis on cis-regulatory sites, non-coding RNAs, and large-scale structural alterations. Read more on the <a href=\"https://dcc.icgc.org/pcawg\" target=\"_blank\">project website</a>.<br>This is a subset featuring RNA-seq transcription profiling data of 27 cancer subtypes in 19 tissues. Some donors have matched normal tissue. As general reference, a subset of normal tissue samples from the GTEx project were included in this experiment.

2020-02-05 | E-MTAB-5200 | biostudies-arrayexpress

The International Cancer Genome project: Pan-Cancer Analysis of Whole Genomes (PCAWG)- Alternative view by individual

Project description:The Pan-Cancer Analysis of Whole Genomes (PCAWG) study is an international collaboration to identify common patterns of mutation in more than 2,800 cancer whole genomes from the International Cancer Genome Consortium. Building upon previous work which examined cancer coding regions, this project is exploring the nature and consequences of somatic and germline variations in both coding and non-coding regions, with specific emphasis on cis-regulatory sites, non-coding RNAs, and large-scale structural alterations. Read more on the <a href=\"https://dcc.icgc.org/pcawg\" target=\"_blank\">project website</a>.<br>This is a subset featuring RNA-seq transcription profiling data of 27 cancer subtypes in 19 tissues. Some donors have matched normal tissue.<br>This is the alternative view of the experiment for Expression Atlas to show gene expression per donor.

2020-02-05 | E-MTAB-5423 | biostudies-arrayexpress

ICGC PanCancer Analysis of Whole Genomes

Project description:The Pancancer Analysis of Whole Genomes (PCAWG) study is an international collaboration to identify common patterns of mutation in more than 2,800 cancer whole genomes from the International Cancer Genome Consortium. Building upon previous work which examined cancer coding regions (Cancer Genome Atlas Research Network, The Cancer Genome Atlas Pan-Cancer analysis project, Nat. Genet. 2013 45:1113), this project is exploring the nature and consequences of somatic and germline variations in both coding and non-coding regions, with specific emphasis on cis-regulatory sites, non-coding RNAs, and large-scale structural alterations.

| EGAS00001001692 | EGA

CTCF-Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription

Project description:Spatial genome organization and its effect on transcription remains a fundamental biological question. We applied an advanced ChIA-PET strategy to comprehensively map higher-order chromosome folding and chromatin interactions mediated by CTCF and RNAPII with haplotype specificity and nucleotide resolution in different human cell lineages. We find that CTCF-mediated interaction anchors serve as structural foci for spatial organization of constitutive genes concordant with CTCF-motif orientation, whereas RNAPII interacts within these structures by selectively drawing cell-type-specific genes towards CTCF-foci and forming RNAPII foci for coordinated transcription. Furthermore, allelic-variants linked to disease susceptibility are found to impact chromatin topology and transcriptional regulation. Importantly, 3D-genome simulation suggested a model of chromatin folding around chromosomal axes, where CTCF involves in defining the interface between condensed and open compartments for structural regulation. Our new 3D-genome strategy thus provides novel insights to explore the topological mechanism of human variations and diseases.

2015-12-11 | GSE72816 | GEO

Biop-C: A Method for Chromatin Interactome Analysis of Solid Cancer Needle Biopsy Samples

Project description:Our results demonstrate the utility of our Biop-C method in investigating the 3D genome organization in solid cancers, and the importance of 3D genome organization in regulating oncogenes in nasopharyngeal cancer.

2021-09-03 | GSE166570 | GEO

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