ATAC-Seq on Cohesin mutant HSPCs
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE73206 | GEO | 2015/11/03
SECONDARY ACCESSION(S): PRJNA296371
REPOSITORIES: GEO
Similar Datasets
Project description:Understanding the impact of cohesin mutations on HSPC chromatin structure We examined chromatin structure using ATAC-seq in CD34+ enriched-human HSPC that were transduced with either cohesin WT, mutant or empty vector controls
2015-11-03 | E-GEOD-73206 | biostudies-arrayexpress
Project description:Transciptome analysis of CD34+ enriched human HSPC lentivirally transduced with cohesin WT or mutant CD34+ enriched HSPCs from cord blood were transduced with a constitutive lentiviral vector expressing cohesin WT or mutant tagged to GFP. After 72hrs cells were GFP+ sorted and subjected to downstream microarray protocol.
2015-11-03 | E-GEOD-73224 | biostudies-arrayexpress
Project description:Transciptome analysis of CD34+ enriched human HSPC lentivirally transduced with cohesin WT or mutant
2015-11-03 | GSE73224 | GEO
Project description:Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation, however cohesin-mutant leukemias do not show genomic instability. We hypothesized reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Bi-allelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation, and revealed an absolute requirement for cohesin in hematopoietic stem cell function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose-dependency for cohesin in regulating chromatin structure and hematopoietic stem cell function. ATAC-seq in murine c-kit+ cells for the following genotypes: Smc3 fl/+, Smc3 del/+, Flt3-ITD, Smc3 fl/del Flt3-ITD
2015-09-21 | E-GEOD-73215 | biostudies-arrayexpress
Project description:The functions of cohesin are central to genome integrity, chromosome organization, and transcription regulation through its prevention of premature sister-chromatid separation and the formation of DNA loops. The loading of cohesin onto chromatin depends on the Scc2-Scc4 complex, however, little is known about how it stimulates the cohesin loading activity. Here we determine the large “hook” structure of Scc2 responsible for catalyzing cohesin loading. We identify key Scc2 surfaces that are crucial for DNA binding and for cohesin loading in vivo. Using previously determined structures and modeling, we derive a pseudo-atomic structure of the full-length Scc2-Scc4 complex. Finally, our crosslinking and electron microscopy analyses reveal that Scc2-Scc4 utilizes its modular structure to make multiple contacts with a folded cohesin at an interface created by the cohesin head-hinge interaction.
2017-01-11 | PXD004692 | Pride
Project description:Mammalian circadian rhythm is established by the negative feedback loops consisting of a set of clock genes, which lead to the circadian expression of thousands of downstream genes. As genome-wide transcription is organized under the high-order chromosome structure, it is unclear how circadian gene expression is influenced by chromosome structure. In this study, we focus on the function of chromatin structure proteins cohesin as well as CTCF (CCCTC-binding factor) in circadian rhythm. We analyzed the interactome of a Bmal1-bound enhancer upstream of a clock gene, Nr1d1, by 4C-seq and observed that cohesin binding sites are enriched in the interactome. Integrating circadian transcriptome data and cistrome data, we found that cohesin-CTCF co-binding sites tend to insulate the phases of circadian oscillating genes while cohesin-non-CTCF sites facilitate the interaction between circadian enhancer and promoter. A coarse-grained model integrating the long-range effect of cohesin and CTCF markedly improved our mechanistic understanding of circadian gene expression. This model is subsequently supported by our RNA-seq data from cohesin knockout cells. Cohesin is required at least in part for driving the circadian gene expression by facilitating the enhancer-promoter looping. Taken together, our study provided a novel insight into the relationship between circadian transcriptome and the high-order chromosome structure. 4C-seq of a Bmal1 enhancer in mouse liver
2016-04-04 | E-GEOD-68830 | biostudies-arrayexpress
Project description:Mammalian circadian rhythm is established by the negative feedback loops consisting of a set of clock genes, which lead to the circadian expression of thousands of downstream genes. As genome-wide transcription is organized under the high-order chromosome structure, it is unclear how circadian gene expression is influenced by chromosome structure. In this study, we focus on the function of chromatin structure proteins cohesin as well as CTCF (CCCTC-binding factor) in circadian rhythm. We analyzed the interactome of a Bmal1-bound enhancer upstream of a clock gene, Nr1d1, by 4C-seq and observed that cohesin binding sites are enriched in the interactome. Integrating circadian transcriptome data and cistrome data, we found that cohesin-CTCF co-binding sites tend to insulate the phases of circadian oscillating genes while cohesin-non-CTCF sites facilitate the interaction between circadian enhancer and promoter. A coarse-grained model integrating the long-range effect of cohesin and CTCF markedly improved our mechanistic understanding of circadian gene expression. This model is subsequently supported by our RNA-seq data from cohesin knockout cells. Cohesin is required at least in part for driving the circadian gene expression by facilitating the enhancer-promoter looping. Taken together, our study provided a novel insight into the relationship between circadian transcriptome and the high-order chromosome structure. RNA-Seq in WT and Smc3-/- mouse embryonic fibroblast cells
2016-04-04 | E-GEOD-68831 | biostudies-arrayexpress
Project description:Mammalian circadian rhythm is established by the negative feedback loops consisting of a set of clock genes, which lead to the circadian expression of thousands of downstream genes. As genome-wide transcription is organized under the high-order chromosome structure, it is unclear how circadian gene expression is influenced by chromosome structure. In this study, we focus on the function of chromatin structure proteins cohesin as well as CTCF (CCCTC-binding factor) in circadian rhythm. We analyzed the interactome of a Bmal1-bound enhancer upstream of a clock gene, Nr1d1, by 4C-seq and observed that cohesin binding sites are enriched in the interactome. Integrating circadian transcriptome data and cistrome data, we found that cohesin-CTCF co-binding sites tend to insulate the phases of circadian oscillating genes while cohesin-non-CTCF sites facilitate the interaction between circadian enhancer and promoter. A coarse-grained model integrating the long-range effect of cohesin and CTCF markedly improved our mechanistic understanding of circadian gene expression. This model is subsequently supported by our RNA-seq data from cohesin knockout cells. Cohesin is required at least in part for driving the circadian gene expression by facilitating the enhancer-promoter looping. Taken together, our study provided a novel insight into the relationship between circadian transcriptome and the high-order chromosome structure. Bmal1 ChIP-Seq in WT mouse embryonic fibroblast cells
2016-04-04 | E-GEOD-77162 | biostudies-arrayexpress
Project description:Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation, however cohesin-mutant leukemias do not show genomic instability. We hypothesized reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Bi-allelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation, and revealed an absolute requirement for cohesin in hematopoietic stem cell function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose-dependency for cohesin in regulating chromatin structure and hematopoietic stem cell function.
2015-09-21 | GSE73215 | GEO
Project description:Cohesin shapes the nuclear chromatin architecture, including enhancer-promoter interactions,
and its components, of which especially STAG2 and RAD21, are frequently mutated in myeloid
malignancies. To elucidate mechanisms of leukemogenesis associated with cohesin mutations
in humans, we comprehensively characterized genetic, epigenetic, transcriptional, and
chromatin conformational changes in acute myeloid leukemia (AML). To corroborate our
findings, we performed complementary siRNA-mediated depletion of STAG2, its paralogue
STAG1 or RAD21 in cord blood-derived CD34+ primary human hematopoietic stem and
progenitor cells (HSPCs). We show that STAG2 mutations consistently lead to the loss of
STAG2 protein and are associated with a specific set of co-occurring mutations, while STAG1
was never mutated in AML. Loss of STAG2 was frequently compensated by STAG1. Still,
specific loci displayed altered cohesin occupancy, gene expression and corresponding changes
in local chromatin activation as measured by H3K27ac enrichment and chromatin accessibility.
High-throughput chromosome conformation capture (in-situ Hi-C) revealed significantly
altered chromatin looping in cohesin-mutated AMLs, including weakened enhancer-promoter
contacts with reduced, cohesin-dependent promoter activity. In HSPCs, we detected
transcriptomic and epigenetic effects overlapping STAG2-mutant AML-specific changes
following STAG2 knockdown (KD), that were not invoked by the depletion of STAG1. We
also found that STAG2 loss in cultured HSPCs impaired the differentiation capacity, especially
erythroid colony formation which maintained HSPC-like gene expression. This work
establishes STAG2 as a key regulator of cohesin-associated chromatin architecture, gene
expression and differentiation in the human hematopoietic system and identifies candidate
target genes that may be implicated in leukemogenesis.
| EGAS00001007405 | EGA