Balancing cohesin eviction and retention prevents aberrant chromosomal interactions, Polycomb-mediated repression, and X-inactivation
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ABSTRACT:
PROVIDER: PRJNA605100 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11033400_1.fastq.gz | Fastqsanger.gz | |||
| SRR11033400_2.fastq.gz | Fastqsanger.gz | |||
| SRR11033401_1.fastq.gz | Fastqsanger.gz | |||
| SRR11033401_2.fastq.gz | Fastqsanger.gz | |||
| SRR11033402_1.fastq.gz | Fastqsanger.gz |
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Project description:Depletion of architectural factors globally alters chromatin structure, but only modestly affects gene expression. We revisit the structure-function relationship using the inactive X chromosome (Xi) as a model. We investigate cohesin imbalances by forcing its depletion or retention using degron-tagged RAD21 (cohesin subunit) or WAPL (cohesin release factor). Interestingly, cohesin loss disrupts Xi superstructure, unveiling superloops between escapee genes, with minimal effect on gene repression. By contrast, forced cohesin retention markedly affects Xi superstructure and compromises spreading of Xist RNA-Polycomb complexes, attenuating Xi silencing. Effects are greatest at distal chromosomal ends, where looping contacts with the Xist locus are weakened. Surprisingly, cohesin loss created an ?Xi superloop? and cohesin retention created ?Xi megadomains? on the active X. Across the genome, a proper cohesin balance protects against aberrant inter-chromosomal interactions and tempers Polycomb-mediated repression. We conclude that a balance of cohesin eviction and retention regulates X-inactivation and inter-chromosomal interactions across the genome.
2021-03-15 | GSE144834 | GEO
Project description:Depletion of architectural factors globally alters chromatin structure but only modestly affects gene expression. We revisit the structure-function relationship using the inactive X chromosome (Xi) as a model. We investigate cohesin imbalances by forcing its depletion or retention using degron-tagged RAD21 (cohesin subunit) or WAPL (cohesin release factor). Cohesin loss disrupts the Xi superstructure, unveiling superloops between escapee genes with minimal effect on gene repression. By contrast, forced cohesin retention markedly affects Xi superstructure, compromises spreading of Xist RNA-Polycomb complexes, and attenuates Xi silencing. Effects are greatest at distal chromosomal ends, where looping contacts with the Xist locus are weakened. Surprisingly, cohesin loss creates an Xi superloop, and cohesin retention creates Xi megadomains on the active X chromosome. Across the genome, a proper cohesin balance protects against aberrant inter-chromosomal interactions and tempers Polycomb-mediated repression. We conclude that a balance of cohesin eviction and retention regulates X inactivation and inter-chromosomal interactions across the genome.
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Project description:A major class of chemotherapeutics targets topoisomerase II for DNA double-strand breaks and cancer cell elimination. We compare four members of this class?the anthracyclines doxorubicin, daunorubicin and aclarubicin that does not induce DNA breaks?and a different compound, etoposide. We define a novel activity for anthracyclines: histone eviction from open chromosomal areas. Since histone variant H2AX is also evicted, DNA damage response is attenuated when compared to etoposide. Histone eviction also affects the epigenetic code and deregulates the transcriptome in cancer cells and organs such as the heart. Histone eviction by anthracyclines can drive apoptosis of topoisomerase-negative acute myeloid leukemia blasts in patients. Doxo- and daunorubicin combine the activities of two anti-cancer drugs: etoposide for DNA damage and aclarubicin for histone eviction. We define a novel mechanism of action of anti-cancer drugs doxo- and daunorubicin on chromatin biology with profound consequences on DNA damage responses, epigenetics, transcription, side effects and anti-cancer activities. Comparison of histone occupancy of cells or tissues treated with topoisomerase II inhibitors to un-treated ones by FAIRE-seq.
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Project description:Chaperones, nucleosome remodeling complexes and histone acetyltransferases have been implicated in nucleosome disassembly at promoters of particular yeast genes, but whether these co-factors function ubiquitously, and the impact of nucleosome eviction on transcription genome-wide, are poorly understood. We used chromatin immunoprecipitation of histone H3 and RNA polymerase II (Pol II) in mutants lacking single or multiple co-factors to address these issues for ~200 genes belonging to the Gcn4 transcriptome, of which ~70 exhibit marked reductions in H3 promoter occupancy on induction by amino acid starvation. Examining four target genes in a panel of mutants indicated that SWI/SNF, Gcn5, the Hsp70 co-chaperone Ydj1, and chromatin-associated factor Yta7 are required downstream of Gcn4 binding for robust H3 eviction in otherwise wild-type cells. Using ChIP-seq to interrogate all 70 exemplar genes in single, double and triple mutants implicated Gcn5, Snf2 and Ydj1 in H3 eviction at most, but not all Gcn4 target promoters, with Gcn5 generally playing the greatest role and Ydj1 the least. Remarkably, these 3 co-factors cooperate similarly in H3 eviction at virtually all yeast promoters. Defective H3 eviction in co-factor mutants was coupled with reduced Pol II occupancies for the Gcn4 transcriptome and the most highly expressed uninduced genes, but the relative Pol II levels at most genes were unaffected or even elevated. These findings indicate that nucleosome eviction is crucial for robust transcription of highly expressed genes, but that other steps in gene activation are more rate-limiting for most other yeast genes. Chromatin immunoprecipitated DNA from WT (induced(+SM) and uninduced(no SM)) and mutants (induced(+SM)) followed by paired-end sequencing. Nucleosomal DNA obtained by MNase digestion were also subjected to paired-end sequencing.
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Project description:The DNA-binding protein CTCF and the cohesin complex function together to shape chromatin architecture in mammalian cells, but the molecular details of this process remain unclear. We demonstrate that a 79 amino acid region within the CTCF N-terminal domain but not the C-terminus is necessary for cohesin positioning at CTCF binding sites and chromatin loop formation. However, the N-terminus of CTCF, when fused to artificial zinc fingers that do not bind to CTCF DNA binding sites was not sufficient to redirect cohesin to different genomic locations, indicating that cohesin positioning by CTCF does not involve direct protein-protein interactions with cohesin subunits. BORIS (CTCFL), a germline-specific paralog of CTCF was unable to anchor cohesin to CTCF DNA binding sites. Furthermore, CTCF-BORIS Chimeric constructs provided evidence that both the first two CTCF zinc fingers and, likely, the 3D geometry of CTCF-DNA complexes are involved in cohesin retention. Moreover, we were able to convert BORIS into CTCF with respect to cohesin positioning, thus providing additional molecular details of the cohesin retention function of CTCF. Our data suggest that the N-terminus of CTCF and the 3D spatial conformation of the CTCF-DNA complex act as a roadblock to constrain cohesin movement along DNA.
2020-01-01 | GSE136122 | GEO
Project description:Nucleosomes are the principal packaging units of chromatin and critical for gene regulation and genome stability. In mammals, a subset of nucleosomes fail to be replaced by protamines during spermatogenesis and are retained in mature spermatozoa providing opportunities for paternal epigenetic transmission. In humans, the remaining 10% localize at regulatory elements of genes. To assess evolutionary conservation and to dissect the molecular logic underlying nucleosome retention, we determined the genome wide nucleosome occupancy in mouse spermatozoa that only contain 1% residual histones. In striking contrast to mammalian somatic cells and haploid round spermatids, we observe high enrichment of nucleosomes at CpG-rich sequences throughout the genome, at conserved regulatory sequences as well as at intra- and intergenic regions and repetitive DNA. This preferred occupancy occurs mutually exclusive with DNA methylation both in mouse and human sperm. At unmethylated CpG-rich sequences, residing nucleosomes are largely composed of the H3.3 histone variant, and trimethylated at lysine 4 (H3K4me3). Both canonical H3.1/H3.2 and H3.3 variant histones are present at promoters marked by Polycomb-mediated H3K27me3, which is strongly predictive for gene repression in pre-implantation embryos. Our data indicate important roles of DNA sequence composition, DNA methylation, variant H3.3 and canonical H3.1/H3.2 histones and associated modifications in nucleosome retention versus eviction during the histone-to-protamine remodeling process in elongating spermatids and potentially in epigenetic inheritance by nucleosomes between generations. Identification of histone, histone variant and histone modification states in round spermatids and sperm
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Project description:To ensure proper gene regulation within constrained nuclear space, chromosomes facilitate access to transcribed regions, while compactly packaging all other information. Recent studies revealed that chromosomes are organized into megabase-scale domains that demarcate active and inactive genetic elements, suggesting that compartmentalization is important for genome function. Here, we show that very specific long-range interactions are anchored by cohesin/CTCF sites, but not cohesin-only or CTCF-only sites, to form a hierarchy of chromosomal loops. These loops demarcate topological domains and form intricate internal structures within them. Post-mitotic nuclei deficient for functional cohesin exhibit global architectural changes associated with loss of cohesin/CTCF contacts and relaxation of topological domains. Transcriptional analysis shows that this cohesin-dependent perturbation of domain organization leads to widespread gene deregulation of both cohesin-bound and non-bound genes. Our data thereby support a role for cohesin in the global organization of domain structure and suggest that domains function to stabilize the transcriptional programmes within them.
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