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

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

PROVIDER: PRJNA327559 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR3737290_1.fastq.gz	Fastqsanger.gz
	SRR3737290_2.fastq.gz	Fastqsanger.gz
	SRR3737291_1.fastq.gz	Fastqsanger.gz
	SRR3737291_2.fastq.gz	Fastqsanger.gz
	SRR3737292_1.fastq.gz	Fastqsanger.gz

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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]

2017-02-24 | GSE83960 | GEO

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

Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation

Project description:Additional Sex Combs Like 1 (ASXL1) is frequently mutated in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). Although loss of ASXL1 promotes hematopoietic transformation, there is growing evidence that ASXL1 mutations might confer an alteration of function. Here we identify that physiological expression of a C-terminal truncated Asxl1 mutant in vivo using conditional knock-in (KI) results in myeloid skewing, age-dependent anemia, thrombocytosis, and morphologic dysplasia. Although expression of mutant Asxl1 altered the functions of hematopoietic stem cells (HSCs), it maintained their survival in competitive transplantation assays and increased susceptibility to leukemic transformation by co-occurring RUNX1 mutation or viral insertional mutagenesis. KI mice displayed substantial reductions in H3K4me3 and H2AK119Ub without significant reductions in H3K27me3, distinct from the effects of Asxl1 loss. ChIP-seq analysis demonstrated opposing effects of wildtype and mutant Asxl1 on H3K4me3. These findings reveal that ASXL1 mutations confer HSCs with an altered epigenome and increase susceptibility for leukemic transformation, presenting a novel model for CHIP.

2018-02-28 | GSE111067 | GEO

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

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

2017-02-24 | GSE83962 | GEO

Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119

Project description:Mutations in additional sex combs like 1 (ASXL1) confer poor prognosis in myeloid malignancies and are also found in pre-malignant clonal hematopoiesis of indeterminate potential (CHIP). However, the mechanisms by which these mutations contribute to disease initiation remain unresolved and therapeutic targeting has remained elusive. Here, we demonstrate that ASXL1 mutations are frequently founding lesions in acute myeloid leukemia (AML) and lead to the expression of a functional, truncated protein. We developed a human disease model that faithfully recapitulates ASXL1-mutant CHIP with increased self-renewal and in vivo competitive advantage that can spontaneously progress to a lethal myeloid malignancy. We determined that truncated ASXL1 leads to global redistribution of the repressive chromatin mark H2AK119Ub, increased chromatin accessibility, and activation of both myeloid and stem cell gene expression programs. Finally, we identified dysregulation of H2AK119Ub as a therapeutic vulnerability and demonstrated that ASXL1-mutant cells are vulnerable to inhibition of the PRC1 complex.

2024-02-07 | GSE190738 | GEO

Mus musculus

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

| PRJNA327562 | ENA

Mus musculus

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

| PRJNA327564 | ENA

Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway

Project description:Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.

2021-02-08 | MSV000086816 | MassIVE

RNA-seq and ChIP-seq data of ASXL1/2 in Hematopoiesis

Project description:RNA-seq and ChIP-seq data of ASXL1/2 in Hematopoiesis

| PRJNA328983 | ENA