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Transcription-driven cohesin accumulation is associated with secretory phenotype of senescence [ChIP-Seq]

ABSTRACT: Senescence is a stable form of cell cycle arrest that is triggered in response to various pathophysiological stimuli. The three-dimensional structure of senescent cells has been previously characterised, mostly in terms of macro-domains or changes between large heterochromatic regions. In the present body of work, using a combination of HiC and targetted Capture Hi-C, we aimed to investigate the association between gene expression and local chromatin structure in senescence, particularly focusing on enhancer-promoter (EP) interactions. We show that many EP contacts are rewired in RAS-induced Senescence compared to ‘normal’, growing cells and that these are associated with cohesin binding changes and possible loop re-organisation. The genes affected by altered chromatin interactions correspond to the two main axes of senescence gene regulation: cell cycle and inflammation. Our findings are potentially relevant during ageing and in cancers with cohesin mutations, where cell cycle and inflammation are also deregulated.

ORGANISM(S): Homo sapiens

PROVIDER: GSE135088 | GEO | 2020/10/05

REPOSITORIES: GEO

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Transcription-driven cohesin accumulation is associated with secretory phenotype of senescence [HiC]

Project description:Senescence is a stable form of cell cycle arrest that is triggered in response to various pathophysiological stimuli. The three-dimensional structure of senescent cells has been previously characterised, mostly in terms of macro-domains or changes between large heterochromatic regions. In the present body of work, using a combination of HiC and targetted Capture Hi-C, we aimed to investigate the association between gene expression and local chromatin structure in senescence, particularly focusing on enhancer-promoter (EP) interactions. We show that many EP contacts are rewired in RAS-induced Senescence compared to ‘normal’, growing cells and that these are associated with cohesin binding changes and possible loop re-organisation. The genes affected by altered chromatin interactions correspond to the two main axes of senescence gene regulation: cell cycle and inflammation. Our findings are potentially relevant during ageing and in cancers with cohesin mutations, where cell cycle and inflammation are also deregulated.

2020-10-05 | GSE135090 | GEO

Inflammation and tumor susceptibility in skin cancer

Project description:This SuperSeries is composed of the following subset Series: GSE12248: Genetic architecture of murine skin inflammation and tumor susceptibility GSE21247: Network Analysis of Skin Tumor Progression Identifies a Rewired Genetic Architecture Affecting Inflammation and Tumor Susceptibility (carcinomas) GSE21263: Network Analysis of Skin Tumor Progression Identifies a Rewired Genetic Architecture Affecting Inflammation and Tumor Susceptibility (papillomas) GSE26273: Network Analysis of Skin Tumor Progression Identifies a Rewired Genetic Architecture Affecting Inflammation and Tumor Susceptibility (aCGH) Refer to individual Series

2010-12-22 | E-GEOD-21264 | biostudies-arrayexpress

The Senescent Methylome and its relationship with cancer, ageing, and germline genetic variation in humans (methylation experiment 2)

Project description:Cellular senescence is a stable arrest of proliferation and is considered a key component of processes associated with carcinogenesis and other ageing-related phenotypes. However, till now, biological markers that define senescence on a genome-wide scale have been limited. Here, we report a DNA methylomic analysis of actively dividing and deeply senescent normal human epithelial cells, identifying 3,852 senescence-associated differentially methylated positions (senDMPs). We find that this human senDMP signature is positively and significantly correlated with both cancer and ageing-associated methylomic dynamics. We also identify germline genetic variants, including those associated with the p16INK4A locus, that are associated with the presence of in vivo senDMP signatures. Importantly, we also demonstrate that the senDMP signature can be effectively reversed in a newly-developed protocol of transient cellular rejuvenation. The senDMP signature has significant potential for understanding some of the key (epi)genetic etiological factors that lead to cancer and age-related diseases in humans. Bisulphite converted DNA from the HMECs at early passage (EP), deep senescence (DS), deep senescence + p16 siRNA (DS+p16siRNA) at two different time points and FACS for cell cycle at EP were hybridised to the Illumina Infinium 450k Human Methylation Beadchip

2015-07-26 | E-GEOD-69046 | biostudies-arrayexpress

The Senescent Methylome and its relationship with cancer, ageing, and germline genetic variation in humans (methylation experiment 1)

2015-07-26 | E-GEOD-56719 | biostudies-arrayexpress

Cohesin interacts with a panoply of splicing factors required for cell cycle progression and genomic organization

Project description:The cohesin complex regulates sister chromatid cohesion, chromosome organization, gene expression, and DNA repair. Here we report that endogenous human cohesin interacts with a panoply of splicing factors and RNA binding proteins, including diverse components of the U4/U6.U5 tri-snRNP complex and several splicing factors that are commonly mutated in cancer. The interactions are enhanced during mitosis, and the interacting splicing factors and RNA binding proteins follow the cohesin cycle and prophase pathway of regulated interactions with chromatin. Depletion of cohesin-interacting splicing factors results in stereotyped cell cycle arrests and alterations in genomic organization. These data support the hypothesis that splicing factors and RNA binding proteins control cell cycle progression and genomic organization via regulated interactions with cohesin and chromatin.

2018-05-17 | GSE114539 | GEO

Wapl controls higher-order chromatin structure in interphase chromosomes (gene expression)

Project description:Mammalian genomes contain several billion base pairs of DNA which are packaged in chromatin fibers. At selected gene loci, cohesin complexes have been proposed to arrange chromatin fibers into higher-order structures, but it is poorly understood how cohesin performs this task, how important this function is for determining the structure of chromosomes, and how this process is regulated to allow changes in gene expression. Here we show that the cohesin release factor Wapl controls chromatin structure and gene regulation at numerous loci throughout the mouse genome. Conditional deletion of the Wapl gene leads to stable accumulation of cohesin on chromatin, chromatin compaction, altered gene expression, cell cycle delay, chromosome segregation defects and embryonic lethality. In Wapl deficient chromosomes, cohesin accumulates in an axial domain, similar to how condensins form a M-bM-^@M-^\scaffoldM-bM-^@M-^] in mitotic chromosomes. We propose that Wapl controls chromatin structure and gene regulation by determining the residence time with which cohesin binds to DNA. 4 biological replicates for each genotype (Wapl +/F; Wapl -/F) treated with/without 4-OHT =16 samples

2013-08-09 | E-GEOD-41460 | biostudies-arrayexpress

Wapl controls higher-order chromatin structure in interphase chromosomes (ChIP-Seq)

Project description:Mammalian genomes contain several billion base pairs of DNA which are packaged in chromatin fibers. At selected gene loci, cohesin complexes have been proposed to arrange chromatin fibers into higher-order structures, but it is poorly understood how cohesin performs this task, how important this function is for determining the structure of chromosomes, and how this process is regulated to allow changes in gene expression. Here we show that the cohesin release factor Wapl controls chromatin structure and gene regulation at numerous loci throughout the mouse genome. Conditional deletion of the Wapl gene leads to stable accumulation of cohesin on chromatin, chromatin compaction, altered gene expression, cell cycle delay, chromosome segregation defects and embryonic lethality. In Wapl deficient chromosomes, cohesin accumulates in an axial domain, similar to how condensins form a “scaffold” in mitotic chromosomes. We propose that Wapl controls chromatin structure and gene regulation by determining the residence time with which cohesin binds to DNA. ChIP-Seq using two different antibodies (CTCF, Smc3); one (CTCF) and two (Smc3) replicates; two different genotypes (Wapl +/delta, Wapl -/delta). The control sample is a single-replicate INPUT for each genotype.

2013-08-09 | E-GEOD-41602 | biostudies-arrayexpress

Balancing cohesin eviction and retention prevents aberrant chromosomal interactions, Polycomb-mediated repression, and X-inactivation

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

Rad21 is the core subunit of cohesin complex in directing genome organization

Project description:In eukaryotes, the nuclear chromatin in the interphase is a hierarchical organization. Previous studies have suggested that cohesin-DNA interactions play important architectural functions for chromatin structure in the interphase. In this study, we applied super-resolution imaging, single-molecule imaging to measure the distribution of cohesin subunits. Hi-C and RNA-seq were used to reveal the 3D genome structures alterations and the relationship with breast cancer upon Rad21 up-regulation. Hi-C experiment showed that the contact frequency of short distance was increased while that of long distance was decreased in the absence of Rad21 up-regulation. Chromatin interactions between A and B compartments increased and compartmentalization strength was reduced significantly upon Rad21 up-regulation. Correspondingly, accumulated contacts were shown at TAD corners and inter-TAD interactions increased. These observations support cohesin loop extrusion model and lead us to propose the unique role of Rad21-loader interaction in cohesin loading and further cohesin extrusion. Moreover, we combined transcriptome changes and chromatin structure alterations upon Rad21 up-regulation and revealed the correlation between Rad21 and breast cancer by affecting chromatin architecture.

2022-05-01 | GSE183186 | GEO

Cohesin is a key determinant of interphase chromosome domain architecture (HiC)

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 programs within them. Hi-C, ChIP-Seq and RNA-Seq experiments were conducted in mouse neural stem cells and mouse astrocytes

2013-12-11 | E-GEOD-49017 | biostudies-arrayexpress

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