Inter-chromosomal contacts demarcate genome topology along a spatial gradient
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PROVIDER: PRJNA1013014 | ENA |
REPOSITORIES: ENA
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Project description:Non-homologous chromosomal contacts (NHCCs) between different chromosomes participate considerably in gene and genome regulation. However, due to analytical challenges, NHCCs are currently considered as singular, stochastic events, and their extent and fundamental principles across cell types and sexes remain controversial. To determine the fundamental properties of NHCCs, we developed a supervised and unsupervised learning algorithm, termed Signature. Signature revealed 40,282 NHCCs and their properties across 62 Hi-C datasets of 53 diploid human cell types. Genomic regions of NHCCs are gene-dense, highly expressed, and harbor genes for cell-specific and sex-specific functions. Extensive inter-telomeric and inter-centromeric clustering occurs across cell types and 61 NHCCs are consistently found at the nuclear speckles. These constitutive ‘anchor loci’ facilitate an axis of genome activity whilst cell-type-specific NHCCs act in discrete hubs. Our results suggest that non-random chromosome positioning is supported by constitutive NHCCs that shape genome topology along an off-centered spatial gradient of genome activity.
2024-10-02 | GSE242273 | GEO
Project description:The eukaryotic nucleus not only encloses meters of DNA, but also requires DNA to be differentially packaged in a cell-specific manner. Advances in chromosome-capture techniques have made great progress in understanding intra-chromosomal interactions. Yet, the mechanistic identities of homologous or non-homologous inter-chromosomal contacts (HCCs or NHCCs) remain elusive. Recently, two long non-coding RNA loci, CISTR-ACT and FIRRE, have been observed at NHCCs and implicated in human disease. Based on single nucleotide polymorphisms (SNPs), we developed an allele-specific CRISPR live-cell DNA imaging technique, named SNP-CLING, to describe primary locus characteristics across space and time. We observed allele-specific gene positioning, frequencies of HCCs or NHCCs, their motility and stability, and their positioning at the distinct sub-nuclear compartment of the nucleolus. Collectively, we define allele-specific locus properties and dynamics, and uncover an important new layer of genome organization in live cells.
2019-01-31 | GSE99657 | GEO
Project description:Inter-organelle membrane contacts especially mitochondria-endoplasmic reticulum contacts (MERC) conduct important biological functions including exchange of lipids and ions, and modulation of membrane dynamics. Alterations of inter-organelle membrane contacts have been implicated with the pathogenesis of diseases, such as neurodegenerative diseases, cancers and type 2 diabetes. However, the protein compositions of inter-organelle contacts remain largely unknown as no biomarker has been discovered and it’s difficult to purify intact inter-organelle contact proteins. Here, we applied a systematic approach to probe the spatial proteome of MERC in living cells by combining the bimolecular fluorescence complementation assay and a proximity labeling strategy based on APEX2. As a result, we discovered 403 highly confident MERC proteins including many well-known MERC proteins and a variety of novel protein species as well. We further validated that WFS1, BAG2, SPTLC1 and GLUD1 are enriched at MERC with high resolution fluorescent imaging. Our study provides a powerful tool to characterize the spatial proteomes of inter-organelle membrane contacts in living cells.
2023-10-24 | PXD035801 | Pride
Project description:Heterobifunctional small molecule degraders that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. However, we currently lack a detailed understanding of the molecular basis for target recruitment and selectivity, which is critically required to enable rational design of degraders. Here we utilize comprehensive characterization of the ligand dependent CRBN/BRD4 interaction to demonstrate that binding between proteins that have not evolved to interact is plastic. Multiple X-ray crystal structures show that plasticity results in several distinct low energy binding conformations, which are selectively bound by ligands. We demonstrate that computational protein-protein docking can reveal the underlying inter-protein contacts and inform the design of the first BRD4 selective degrader that can discriminate between highly homologous BET bromodomains. Our findings that plastic inter-protein contacts confer selectivity for ligand-induced protein dimerization provide a conceptual framework for the development of heterobifunctional ligands.
2018-05-23 | PXD008674 | Pride
Project description:Heterobifunctional small molecule degraders that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. However, we currently lack a detailed understanding of the molecular basis for target recruitment and selectivity, which is critically required to enable rational design of degraders. Here we utilize comprehensive characterization of the ligand dependent CRBN/BRD4 interaction to demonstrate that binding between proteins that have not evolved to interact is plastic. Multiple X-ray crystal structures show that plasticity results in several distinct low energy binding conformations, which are selectively bound by ligands. We demonstrate that computational protein-protein docking can reveal the underlying inter-protein contacts and inform the design of the first BRD4 selective degrader that can discriminate between highly homologous BET bromodomains. Our findings that plastic inter-protein contacts confer selectivity for ligand-induced protein dimerization provide a conceptual framework for the development of heterobifunctional ligands.
2018-05-16 | PXD008689 | Pride
Project description:Expression of the clusters of rDNA genes influences pluripotency, but the underlying mechanisms are not known yet. The clusters shape inter-chromosomal contacts with numerous genes controlling differentiation in human cells. The fact suggests the possible role of these contacts in formation of 3D chromosomal structures and regulation of gene expression in development. We used human leukemia K562 cells induction to erythroid differentiation in order to study the genome-wide changes in inter-chromosomal rDNA-associated contacts.
2023-09-11 | GSE232392 | GEO
Project description:Contacts between organelles create microdomains that play major roles in regulating key intracellular activities and signaling pathways, but whether they also directly regulate systemic cellular activities, remains unknown. Here, we report the ultrastructural organization and dynamics of a new type of inter-organelle contact which is formed by rough-Endoplasmic Reticulum that is closely wrapped around the mitochondrion (wrappER). To elucidate the in vivo function of this inter-organelle association, mouse liver fractions enriched in wrappER-associated-mitochondria were analyzed in parallel by transcriptomics, proteomics, and lipidomics. The biochemical signature of the wrappER points to an unexpected role in the biogenesis of very-low-density lipoproteins (VLDLs). Altering wrappER-mitochondria contacts curtails liver VLDL secretion and increases hepatic fatty acids, lipid droplets and neutral lipid content. Conversely, acute liver-specific ablation of Mttp, the most upstream regulator of VLDL biogenesis, mirrors this hepatic dyslipidemia phenotype and promotes remodelling of the wrappER-mitochondria contact. The participation of liver wrappER-mitochondria contacts in VLDL biology reveals a role of inter-organelle contacts in systemic lipid homeostasis.
2021-03-15 | PXD021826 | Pride
Project description:Inter-chromosomal contacts of the 16p11.2 locus connect with gene expression changes of Pcdh genes in autism spectrum disorder
| PRJNA613480 | ENA
Project description:Contacts between organelles create microdomains that play major roles in regulating key intracellular activities and signaling pathways, but whether they also regulate systemic functions remains unknown. Here, we report the ultrastructural organization and dynamics of the inter-organellar contact established by rough-Endoplasmic Reticulum closely wrapped around the mitochondria (wrappER). To elucidate the in vivo function of this contact, mouse liver fractions enriched in wrappER-associated-mitochondria are analyzed by transcriptomics, proteomics and lipidomics. The biochemical signature of the wrappER points to a role in the biogenesis of very-low-density lipoproteins (VLDL). Altering wrappER-mitochondria contacts curtails VLDL secretion and increases hepatic fatty acids, lipid droplets and neutral lipid content. Conversely, acute liver-specific ablation of Mttp, the most upstream regulator of VLDL biogenesis, recapitulates this hepatic dyslipidemia phenotype and promotes remodelling of the wrappER-mitochondria contact. The discovery that liver wrappER-mitochondria contacts participate in VLDL biology suggests an involvement of inter-organelle contacts in systemic lipid homeostasis.
2021-03-15 | GSE134777 | GEO
Project description:Chromosomes are folded into highly compacted structures to accommodate physical constraints within nuclei and to regulate access to genomic information. Recently, global mapping of pairwise contacts showed that loops anchoring topological domains (TADs), are highly conserved between cell types and species. Whether pairwise loops synergize to form higher order structures is still unclear. Here we develop a conformation capture approach to study higher order organization using chromosomal walks (C-walks) that link multiple genomic loci together into proximity chains. The data captured a hierarchical chromosomal structure at varying scales. Inter-chromosomal contacts constitute only 7-10% of the pairs and are restricted by the TAD structure of the interfacing chromosomes. About half of the C-walks stay within one chromosome, and almost half of these are restricted to intra-TAD spaces. Analysis of nested topological motifs suggests hierarchical chromosomal structure is present also within TADs. Targeted analysis of thousands of 3-walks anchored at strongly expressed genes support nested, rather than hub-like, chromosomal topology at active loci. Polycomb-repressed HOX domains are shown by the same approach to form synergistic hubs. Together, the data suggest that chromosomal territories, TADs, and intra-TAD loops are primarily driven by nested, possibly dynamic, pairwise contacts.
2016-02-04 | GSE77553 | GEO