Cohesin in AML
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE76320 | GEO | 2016/08/09
SECONDARY ACCESSION(S): PRJNA306887
REPOSITORIES: GEO
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Project description:MTD project_description Inflammation and decreased stem cell function characterize organism aging, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells exhibit increased ground-stage NF-κB activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-κB signals, by increasing chromatin accessibility of inter-/intra-genic and enhancer regions. Rad21/NF-κB are required for normal differentiation, but limit self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-κB dependent manner. HSCs from aged mice fail to downregulate Rad21/cohesin and inflammation/differentiation inducing signals in the resolution phase after acute inflammation. and The inhibition of cohesin/NF-κB is sufficient to revert the hypersensitivity of aged HSPCs to inflammation-induced differentiation. During aging, myeloid-biased HSCs with disrupted and naturally occurring reduced expression of Rad21/cohesin are increasingly selected over lymphoid-biased HSCs. Together, Rad21/cohesin mediated NF-κB signaling limits HSPC function during aging and selects for cohesin deficient HSCs with myeloid skewed differentiation.
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Project description:Ubiquitination is a post-translational mechanism of control of diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes including Notch1, c-Myc and cyclin E. We have generated conditional Fbw7 knock-out animals and inactivated the gene in hematopoietic stem cells (HSC) and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects the HSC compartment in a cell-autonomous manner. Fbw7-/- HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7-/- HSC are unable to colonize the thymus leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E are stabilized in the bone marrow of Fbw7 deficient mice. Genome-wide transcriptome studies of Fbw7-/- HSC and hematopoietic progenitors indicate that Fbw7 controls, through the regulation of HSC cell cycle entry, the global transcriptional âsignatureâ that is associated with the quiescent, self-renewing HSC phenotype. Transcriptional consequences of inactivating Fbw7 in LKS cells. Experiment Overall Design: Four samples were analyzed: wild-type (WT) control and Fbw7-deficient (FBW7) Lin-ckit+Sca1+ (LSK) cells, as well as Lin-ckit+Sca1- myeloid progenitor (MP) cells, which served as a control for LSK-enriched/specific genes. Total bone marrow cells were pooled from three WT and three FBW7 mice before sorting LSK and MP populations.
2008-06-11 | E-GEOD-11178 | biostudies-arrayexpress
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
Project description:Cohesin loss-of-function mutations are frequently observed in tumors, but the mechanism is unclear. Here, we found that depletion of RAD21, a core subunit of cohesin, leads to massive genome-wide DNA breaks, up to five-fold, and 147 translocation hotspot genes that are co-mutated with cohesin in multiple cancers. Increased DNA damages are independent of RAD21-loss-induced transcription alteration and loop anchor elimination. However, damage-induced chromosomal translocations coincide with the asymmetrically distributed Okazaki fragments of DNA replication, suggesting that RAD21 depletion causes replication stresses evidenced by the slower replication speed and increased stalled forks. Mechanistically, approximately 30% of the human genome exhibits an earlier replication timing after RAD21 depletion, caused by the early initiation of >900 extra dormant origins. Correspondingly, most translocation hotspot genes lie in timing-altered regions. Therefore, we conclude that cohesin dysfunction causes replication stresses induced by excessive DNA replication initiation, resulting in gross DNA damages that may promote tumorigenesis.
2023-05-18 | GSE200035 | GEO
Project description:Cohesin loss-of-function mutations are frequently observed in tumors, but the mechanism is unclear. Here, we found that depletion of RAD21, a core subunit of cohesin, leads to massive genome-wide DNA breaks, up to five-fold, and 147 translocation hotspot genes that are co-mutated with cohesin in multiple cancers. Increased DNA damages are independent of RAD21-loss-induced transcription alteration and loop anchor elimination. However, damage-induced chromosomal translocations coincide with the asymmetrically distributed Okazaki fragments of DNA replication, suggesting that RAD21 depletion causes replication stresses evidenced by the slower replication speed and increased stalled forks. Mechanistically, approximately 30% of the human genome exhibits an earlier replication timing after RAD21 depletion, caused by the early initiation of >900 extra dormant origins. Correspondingly, most translocation hotspot genes lie in timing-altered regions. Therefore, we conclude that cohesin dysfunction causes replication stresses induced by excessive DNA replication initiation, resulting in gross DNA damages that may promote tumorigenesis.
2023-05-18 | GSE199712 | GEO
Project description:Cohesin loss-of-function mutations are frequently observed in tumors, but the mechanism is unclear. Here, we found that depletion of RAD21, a core subunit of cohesin, leads to massive genome-wide DNA breaks, up to five-fold, and 147 translocation hotspot genes that are co-mutated with cohesin in multiple cancers. Increased DNA damages are independent of RAD21-loss-induced transcription alteration and loop anchor elimination. However, damage-induced chromosomal translocations coincide with the asymmetrically distributed Okazaki fragments of DNA replication, suggesting that RAD21 depletion causes replication stresses evidenced by the slower replication speed and increased stalled forks. Mechanistically, approximately 30% of the human genome exhibits an earlier replication timing after RAD21 depletion, caused by the early initiation of >900 extra dormant origins. Correspondingly, most translocation hotspot genes lie in timing-altered regions. Therefore, we conclude that cohesin dysfunction causes replication stresses induced by excessive DNA replication initiation, resulting in gross DNA damages that may promote tumorigenesis.
2023-05-18 | GSE199269 | GEO