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ASXL1 Interacts with the Cohesin Complex to Maintain Chromatid Separation and Gene Expression for Normal Hematopoiesis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE83962 | GEO | 2017/02/24

SECONDARY ACCESSION(S): PRJNA327559

REPOSITORIES: GEO

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ASXL1 interacts with the cohesin complex to maintain chromatid separation and gene expression for normal hematopoiesis.

Project description:ASXL1 is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice; however, the underlying molecular mechanisms remain unclear. We report that ASXL1 interacts with the cohesin complex, which has been shown to guide sister chromatid segregation and regulate gene expression. Loss of Asxl1 impairs the cohesin function, as reflected by an impaired telophase chromatid disjunction in hematopoietic cells. Chromatin immunoprecipitation followed by DNA sequencing data revealed that ASXL1, RAD21, and SMC1A share 93% of genomic binding sites at promoter regions in Lin-cKit+ (LK) cells. We have shown that loss of Asxl1 reduces the genome binding of RAD21 and SMC1A and alters the expression of ASXL1/cohesin target genes in LK cells. Our study underscores the ASXL1-cohesin interaction as a novel means to maintain normal sister chromatid separation and regulate gene expression in hematopoietic cells.

| S-EPMC5249256 | biostudies-literature

ASXL1 Interacts with the Cohesin Complex to Maintain Chromatid Separation and Gene Expression for Normal Hematopoiesis [RNA-Seq]

Project description:ASXL1 is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice, however, the underlying molecular mechanisms remain unclear. Here, we report that ASXL1 interacts with the cohesin complex, which has been shown to guide sister chromotid segregation and to regulate gene expression. Loss of Asxl1 impairs the cohesin function as reflected by an impaired telophase chromatid disjunction in hematopoietic cells. ChIP-seq data revealed that ASXL1, RAD21 and SMC1A share 93% of genomic binding sites at promoter regions in lineage-cKit+ (LK) cells. We have showed that loss of Asxl1 reduced the genome binding of RAD21 and SMC1A, and altered the expression of ASXL1/cohesin target genes in LK cells. Our study underscores the ASXL1-cohesin interaction as a novel means to maintain normal sister chromatid separation and to regulate gene expression in hematopoietic cells.

2017-02-24 | GSE83961 | GEO

ASXL1 Interacts with the Cohesin Complex to Maintain Chromatid Separation and Gene Expression for Normal Hematopoiesis [ChIP-Seq]

Project description:ASXL1 is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice, however, the underlying molecular mechanisms remain unclear. Here, we report that ASXL1 interacts with the cohesin complex, which has been shown to guide sister chromotid segregation and to regulate gene expression. Loss of Asxl1 impairs the cohesin function as reflected by an impaired telophase chromatid disjunction in hematopoietic cells. ChIP-seq data revealed that ASXL1, RAD21 and SMC1A share 93% of genomic binding sites at promoter regions in lineage-cKit+ (LK) cells. We have showed that loss of Asxl1 reduced the genome binding of RAD21 and SMC1A, and altered the expression of ASXL1/cohesin target genes in LK cells. Our study underscores the ASXL1-cohesin interaction as a novel means to maintain normal sister chromatid separation and to regulate gene expression in hematopoietic cells.

2017-02-24 | GSE83960 | GEO

ASXL1 Interacts with the Cohesin Complex to Maintain Chromatid Separation and Gene Expression for Normal Hematopoiesis

Project description:ASXL1 Interacts with the Cohesin Complex to Maintain Chromatid Separation and Gene Expression for Normal Hematopoiesis

| PRJNA327559 | ENA

Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis.

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 that 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. Biallelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation and revealed an absolute requirement for cohesin in hematopoietic stem cell (HSC) 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 HSC function.

| S-EPMC4612085 | biostudies-literature

Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-09-21 | E-GEOD-73218 | biostudies-arrayexpress

Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2015-09-21 | GSE73218 | GEO

Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis [ATAC-Seq]

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

Human SMC5/6 complex promotes sister chromatid homologous recombination by recruiting the SMC1/3 cohesin complex to double-strand breaks.

Project description:The structural maintenance of chromosomes (SMC) family of proteins has been implicated in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR). The SMC1/3 cohesin complex is thought to promote HR by maintaining the close proximity of sister chromatids at DSBs. The SMC5/6 complex is also required for DNA repair, but the mechanism by which it accomplishes this is unclear. Here, we show that RNAi-mediated knockdown of the SMC5/6 complex components in human cells increases the efficiency of gene targeting due to a specific requirement for hSMC5/6 in sister chromatid HR. Knockdown of the hSMC5/6 complex decreases sister chromatid HR, but does not reduce nonhomologous end-joining (NHEJ) or intra-chromatid, homologue, or extrachromosomal HR. The hSMC5/6 complex is itself recruited to nuclease-induced DSBs and is required for the recruitment of cohesin to DSBs. Our results establish a mechanism by which the hSMC5/6 complex promotes DNA repair and suggest a novel strategy to improve the efficiency of gene targeting in mammalian somatic cells.

| S-EPMC1523187 | biostudies-literature

Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis [ATAC-Seq]

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

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