Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

STAG2 Mutations Reshape the Cohesin-Structured Spatial Chromatin Architecture to Drive Gene Regulation in Acute myeloid Leukemia [ATAC-Seq]

ABSTRACT: Cohesin shapes the chromatin architecture, including enhancer-promoter interactions. Its components, especially STAG2 but not its paralogue STAG1, are frequently mutated in myeloid malignancies. To elucidate the underlying mechanisms of leukemogenesis, we comprehensively characterized genetic, epigenetic, transcriptional, and chromatin conformational changes in acute myeloid leukemia (AML) patient samples. Specific loci displayed altered cohesin occupancy, gene expression and local chromatin activation which were not compensated by STAG1. These changes could be linked to disrupted spatial chromatin looping in cohesin-mutated AMLs. We performed complementary depletion of STAG2 or STAG1 in primary human hematopoietic progenitors (HSPCs). We detected effects overlapping STAG2-mutant AML-specific changes following STAG2 knockdown, not invoked by depletion of STAG1. STAG2-deficient HSPCs displayed impaired differentiation capacity and maintained HSPC-like gene expression. This work establishes STAG2 as a key regulator of chromatin contacts, gene expression and differentiation in the hematopoietic system and identifies candidate target genes that may be implicated in human leukemogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE267678 | GEO | 2024/06/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

STAG2 Mutations Reshape the Cohesin-Structured Spatial Chromatin Architecture to Drive Gene Regulation in Acute myeloid Leukemia [ChIP-Seq]

Project description:Cohesin shapes the chromatin architecture, including enhancer-promoter interactions. Its components, especially STAG2 but not its paralogue STAG1, are frequently mutated in myeloid malignancies. To elucidate the underlying mechanisms of leukemogenesis, we comprehensively characterized genetic, epigenetic, transcriptional, and chromatin conformational changes in acute myeloid leukemia (AML) patient samples. Specific loci displayed altered cohesin occupancy, gene expression and local chromatin activation which were not compensated by STAG1. These changes could be linked to disrupted spatial chromatin looping in cohesin-mutated AMLs. We performed complementary depletion of STAG2 or STAG1 in primary human hematopoietic progenitors (HSPCs). We detected effects overlapping STAG2-mutant AML-specific changes following STAG2 knockdown, not invoked by depletion of STAG1. STAG2-deficient HSPCs displayed impaired differentiation capacity and maintained HSPC-like gene expression. This work establishes STAG2 as a key regulator of chromatin contacts, gene expression and differentiation in the hematopoietic system and identifies candidate target genes that may be implicated in human leukemogenesis.

2024-06-18 | GSE268031 | GEO

STAG2 Mutations Reshape the Cohesin-Structured Spatial Chromatin Architecture to Drive Gene Regulation in Acute myeloid Leukemia [Hi-C]

2024-06-18 | GSE267780 | GEO

STAG2 Mutations Reshape the Cohesin-Structured Spatial Chromatin Architecture to Drive Gene Regulation in Acute myeloid Leukemia [bulk RNA-Seq]

2024-06-18 | GSE267679 | GEO

STAG2 Mutations Reshape the Cohesin-Structured Spatial Chromatin Architecture to Drive Gene Regulation in Acute myeloid Leukemia [DNAInputSeq]

2024-06-18 | GSE267683 | GEO

STAG2 Mutations Reshape the Cohesin-Structured Spatial Chromatin Architecture to Drive Gene Regulation in Acute myeloid Leukemia [scRNA-Seq]

2024-06-18 | GSE267682 | GEO

Cohesin Mutations in AML

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

Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation [RNA_3populations_LSK_GMP_CFUE]

Project description:Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show that Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. Chromatin immunoprecipitation (ChIP) sequencing revealed that, although Stag2 and Stag1 bind a shared set of genomic loci, a component of Stag2 binding sites is unoccupied by Stag1, even in Stag2-deficient HSPCs. Although concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to increased self-renewal and reduced HSPC commitment to the B cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation.

2019-09-26 | GSE138006 | GEO

Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation [ChIP_LinNeg_Stag1Stag2CTCF]

2019-09-26 | GSE138005 | GEO

Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation [ATAC_LinNegBM]

2019-09-26 | GSE138004 | GEO

Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation [ATAC_LSK_GMP_CFUE_Stag2KOWT]

2019-09-26 | GSE138003 | GEO