STAG2 promotes CTCF-anchored loop extrusion and cis-promoter and -enhancer interactions
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA550416 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12492700_1.fastq.gz | Fastqsanger.gz | |||
| SRR12492700_2.fastq.gz | Fastqsanger.gz | |||
| SRR12492900_1.fastq.gz | Fastqsanger.gz | |||
| SRR12492900_2.fastq.gz | Fastqsanger.gz | |||
| SRR12492701_1.fastq.gz | Fastqsanger.gz |
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Project description:STAG2, a member of cohesin, is one of the most recurrently mutated genes in human cancer. Here, we investigated STAG2 function in the context of Ewing sarcoma. Using a CRISPR/Cas9 approach, we generated two STAG2 knock-out isogenic clones (A673_SA2m#1 and TC71_SA2m#2) derived from A673 and TC71 STAG2 wild type (WT) Ewing sarcoma cell line. A STAG2 rescue model (A673_SA2r) was generated by correcting the CRISPR mutation in the A673_SA2m#1 model. These STAG1/2 proficient and deficient models were profiled by CTCF HiChIP experiments. STAG2 isogenic models were also profiled by H3K27ac HiChIP experiments. Analyses of HiChIP data allowed to show that STAG2 promotes CTCF-anchored loop extrusion and cis-promoter and -enhancer interactions.
2021-04-29 | GSE133227 | GEO
Project description:Cohesin folds chromosomes via DNA loop extrusion. Cohesin-mediated chromosome loops regulate transcription by shaping long-range enhancer-promoter interactions, among other mechanisms. Mutations of cohesin subunits and regulators cause human developmental diseases termed cohesinopathy. Vertebrate cohesin consists of SMC1, SMC3, RAD21, and either STAG1 or STAG2. To probe the physiological functions of cohesin, we created conditional knockout (cKO) mice with Stag2 deleted in the nervous system. Stag2 cKO mice exhibit growth retardation, neurological defects, and premature death, in part due to insufficient myelination of nerve fibers. Stag2 cKO oligodendrocytes exhibit delayed maturation and downregulation of myelinationrelated genes. Stag2 loss reduces promoter-anchored loops at downregulated genes in oligodendrocytes. Thus, STAG2-cohesin generates promoter-anchored loops at myelinationpromoting genes to facilitate their transcription. Our study implicates defective myelination as a contributing factor to cohesinopathy and establishes oligodendrocytes as a relevant cell type to explore the mechanisms by which cohesin regulates transcription.
2022-08-23 | GSE186893 | GEO
Project description:Cohesin folds chromosomes via DNA loop extrusion. Cohesin-mediated chromosome loops regulate transcription by shaping long-range enhancer-promoter interactions, among other mechanisms. Mutations of cohesin subunits and regulators cause human developmental diseases termed cohesinopathy. Vertebrate cohesin consists of SMC1, SMC3, RAD21, and either STAG1 or STAG2. To probe the physiological functions of cohesin, we created conditional knockout (cKO) mice with Stag2 deleted in the nervous system. Stag2 cKO mice exhibit growth retardation, neurological defects, and premature death, in part due to insufficient myelination of nerve fibers. Stag2 cKO oligodendrocytes exhibit delayed maturation and downregulation of myelinationrelated genes. Stag2 loss reduces promoter-anchored loops at downregulated genes in oligodendrocytes. Thus, STAG2-cohesin generates promoter-anchored loops at myelinationpromoting genes to facilitate their transcription. Our study implicates defective myelination as a contributing factor to cohesinopathy and establishes oligodendrocytes as a relevant cell type to explore the mechanisms by which cohesin regulates transcription.
2022-08-23 | GSE186892 | GEO
Project description:Cohesin folds chromosomes via DNA loop extrusion. Cohesin-mediated chromosome loops regulate transcription by shaping long-range enhancer-promoter interactions, among other mechanisms. Mutations of cohesin subunits and regulators cause human developmental diseases termed cohesinopathy. Vertebrate cohesin consists of SMC1, SMC3, RAD21, and either STAG1 or STAG2. To probe the physiological functions of cohesin, we created conditional knockout (cKO) mice with Stag2 deleted in the nervous system. Stag2 cKO mice exhibit growth retardation, neurological defects, and premature death, in part due to insufficient myelination of nerve fibers. Stag2 cKO oligodendrocytes exhibit delayed maturation and downregulation of myelinationrelated genes. Stag2 loss reduces promoter-anchored loops at downregulated genes in oligodendrocytes. Thus, STAG2-cohesin generates promoter-anchored loops at myelinationpromoting genes to facilitate their transcription. Our study implicates defective myelination as a contributing factor to cohesinopathy and establishes oligodendrocytes as a relevant cell type to explore the mechanisms by which cohesin regulates transcription.
2022-08-23 | GSE186891 | GEO
Project description:Cohesin folds chromosomes via DNA loop extrusion. Cohesin-mediated chromosome loops regulate transcription by shaping long-range enhancer-promoter interactions, among other mechanisms. Mutations of cohesin subunits and regulators cause human developmental diseases termed cohesinopathy. Vertebrate cohesin consists of SMC1, SMC3, RAD21, and either STAG1 or STAG2. To probe the physiological functions of cohesin, we created conditional knockout (cKO) mice with Stag2 deleted in the nervous system. Stag2 cKO mice exhibit growth retardation, neurological defects, and premature death, in part due to insufficient myelination of nerve fibers. Stag2 cKO oligodendrocytes exhibit delayed maturation and downregulation of myelinationrelated genes. Stag2 loss reduces promoter-anchored loops at downregulated genes in oligodendrocytes. Thus, STAG2-cohesin generates promoter-anchored loops at myelinationpromoting genes to facilitate their transcription. Our study implicates defective myelination as a contributing factor to cohesinopathy and establishes oligodendrocytes as a relevant cell type to explore the mechanisms by which cohesin regulates transcription.
2022-08-23 | GSE186890 | GEO
Project description:Eukaryotic genomes are compacted into loops and topologically associating domains (TADs), which contribute to transcription, recombination and genomic stability. Cohesin extrudes DNA into loops that are thought to lengthen until CTCF boundaries are encountered. Little is known about whether loop extrusion is impeded by DNA-bound machines. Here we show that the minichromosome maintenance (MCM) complex is a barrier that restricts loop extrusion in G1 phase. Single-nucleus Hi-C of mouse zygotes revealed that MCM loading reduces CTCF-anchored loops and decreases TAD boundary insulation, suggesting loop extrusion is impeded before reaching CTCF. This effect extends to HCT116 cells, where MCMs affect the number of CTCF-anchored loops and gene expression. Simulations suggest that MCMs are abundant, randomly positioned, partially permeable barriers. Single-molecule imaging shows that MCMs are physical barriers that frequently constrain cohesin translocation in vitro. Remarkably, chimaeric yeast MCMs harbouring a cohesin-interaction motif from human MCM3 induce cohesin pausing, suggesting that MCMs are “active” barriers with binding sites. These findings raise the possibility that cohesin can arrive by loop extrusion at MCMs, which determine the genomic sites at which sister chromatid cohesion is established. Based on in vivo, in silico and in vitro data, we conclude that distinct loop extrusion barriers shape the 3D genome.
2022-03-08 | GSE196496 | GEO
Project description:Eukaryotic genomes are compacted into loops and topologically associating domains (TADs), which contribute to transcription, recombination and genomic stability. Cohesin extrudes DNA into loops that are thought to lengthen until CTCF boundaries are encountered. Little is known about whether loop extrusion is impeded by DNA-bound macromolecular machines. We demonstrate that the replicative helicase MCM is a barrier that restricts loop extrusion in G1 phase. Single-nucleus Hi-C of one-cell embryos revealed that MCM loading reduces CTCF-anchored loops and decreases TAD boundary insulation, suggesting loop extrusion is impeded before reaching CTCF. Single-molecule imaging shows that MCMs are physical barriers that constrain cohesin translocation in vitro. Simulations are consistent with MCMs as abundant, random barriers. We conclude that distinct loop extrusion barriers contribute to shaping 3D genomes.
2022-03-08 | GSE196300 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-04-29 | GSE133228 | GEO
Project description:Cohesin is a key organizer of chromatin folding in eukaryotic cells. Two basic activities of this ring-shaped protein complex are maintenance of sister chromatid cohesion and establishment of long-range DNA-DNA interactions through the process of loop extrusion. Though basic principles of both cohesion and loop extrusion have been described we still do not understand several crucial mechanistic details. One of such unresolved issues is the question of whether a cohesin ring topologically embraces DNA string(s) during loop extrusion. Here we show that cohesin complexes residing on CTCF-occupied genomic sites in mammalian cells do not interact with DNA topologically. We assessed stability of cohesin-dependent loops and cohesin association with chromatin in high ionic strength conditions in G1-synchronised HeLa cells. We found that increased salt concentration completely displaces cohesin from those genomic regions which correspond to CTCF-defined loop anchors. Unsurprisingly, CTCF-anchored cohesin loops also dissipate in these conditions. As topologically-engaged cohesin is considered to be salt-resistant, our data corroborate a non-topological model of loop extrusion.
2021-07-20 | GSE166387 | GEO
Project description:Genome function depends on regulated chromosome folding, and loop extrusion by the protein complex cohesin is essential for this multilayered organization. The chromosomal positioning of cohesin is controlled by transcription, and the complex also localizes to stalled replication forks. However, the role of transcription and replication in chromosome looping remains unclear. Here, we show that reduction of chromosome-bound RNA polymerase weakens normal cohesin loop extrusion boundaries, allowing cohesin to form new long-range chromosome cis interactions. Stress response genes activated by transcription inhibition are also shown to act as new loop extrusion boundaries. Furthermore, cohesin loop extrusion during early S-phase is jointly controlled by transcription and replication units. Together, the results reveal that replication and transcription machineries are chromosome folding regulators that block the progression of loop-extruding cohesin, opening for new perspectives on cohesin’s roles in genome function and stability.
2022-06-15 | GSE162193 | GEO