Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia [ChIP-Seq]

ABSTRACT: The molecular regulation of human hematopoietic stem cell (HSC) maintenance is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance. Through our analyses, we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs differentiate. Strikingly, we show that this transcriptional network is co-opted in high-risk leukemias, thereby enabling these cancers to acquire stem cell properties. Collectively, we illuminate a regulatory network necessary for HSC self-renewal through the study of a rare experiment of nature.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214399 | GEO | 2022/11/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Mitochondrial respiratory chain is essential for hematopoietic stem cell function

Project description:Adult and fetal hematopoietic stem cells (HSCs) display a glycolytic phenotype, which is required for maintenance of stemness; however, whether mitochondrial respiration is required to maintain HSC function is not known. Here we report that loss of the mitochondrial complex III subunit Rieske iron sulfur protein (RISP) in fetal mouse HSCs allows them to proliferate but impairs their differentiation, resulting in anemia and prenatal death. RISP null fetal HSCs displayed impaired respiration resulting in a decreased NAD+/NADH ratio. RISP null fetal HSCs and progenitors exhibited an increase in both DNA and histone methylation concomitant with increases in 2-hydroxyglutarate (2-HG), a metabolite known to inhibit DNA and histone demethylases. RISP inactivation in adult HSCs also impaired respiration resulting in loss of quiescence resulting in severe pancytopenia and lethality. Thus, respiration is dispensable for adult or fetal HSC proliferation, but essential for fetal HSC differentiation and maintenance of adult HSC quiescence.

2017-09-13 | PXD006054 | Pride

Molecular characterization of hematopoietic stem cells after in vitro amplification on biomimetic 3D PDMS cell culture scaffoldsMolecular characterization of hematopoietic stem cells after in vitro amplification on biomimetic 3D PDMS cell culture scaffolds

Project description:Hematopoietic stem cell transplantation (HSCT) is successfully applied since the late 1950s, however, its efficacy still needs to be improved. A promising strategy is to transplant high numbers of pluripotent hematopoietic stem cells (HSCs). Therefore, an advanced ex vivo culture system is needed that supports the proliferation and maintains the pluripotency of HSC to override possible limitations in cell numbers gained from donors. To model the natural HSC niche in vitro and thus, to amplify high numbers of undifferentiated HSCs, we used an optimized HSC cell culture medium in combination with artificial 3D bone marrow-like scaffolds made of polydimethylsiloxane (PDMS). After 14 days in vitro (DIV) cell culture, we performed transcriptome and proteome analysis of the whole cell populations. Ingenuity pathway analysis (IPA) indicated that our 3D PDMS cell culture scaffolds activated interleukin, SREBP, mTOR and FOXO signaling pathways as well as the HSC metabolism, which we confirmed by ELISA, Western blot and metabolic flux analysis. These molecular signaling pathways and HSC metabolism are well known to promote the expansion HSCs and are involved in their pluripotency maintenance. After selection and enrichment of immature CD34-positive/CD38-negative HSCs using FACS sorting, we could confirm our findings by another proteome analysis followed by IPA. Thus, we could show that our 3D bone marrow-like PDMS scaffolds activate key molecular signaling pathways to amplify the numbers of undifferentiated HSC efficiently ex vivo.

2021-11-10 | PXD025849 | Pride

RNA-seq transcriptome analysis of Nestin-GFP-peri and -GFP-retic bone marrow stromal cells

Project description:Cell cycle quiescence is a critical feature contributing to haematopoietic stem cell (HSC) maintenance. Although various candidate stromal cells have been identified as potential HSC niches, the spatial localization of quiescent HSC in the bone marrow (BM) remains unclear. Here, using a novel approach that combines whole-mount confocal immunofluorescence imaging technique and computational modelling to analyse significant tridimensional associations among vascular structures, stromal cells and HSCs, we show that quiescent HSCs associate specifically with small arterioles that are preferentially found in endosteal BM. These arterioles are ensheathed exclusively by rare Nestin-GFP-peri/NG2+ pericytes, distinct from sinusoid-associated Nestin-GFP-retic/LepR+ cells. The present RNA-seq study sought to obtain a comprehensive understanding of the differences between the two distinct HSC cellular niches. mRNA profiles of sorted Nestin-GFP-peri and -GFP-retic bone marrow stromal cells were generated from pooled mice in triplicate by Illumina HiSeq 2000 sequencing.

2013-10-10 | E-GEOD-48764 | biostudies-arrayexpress

MOF directs erythroid fate during hematopoiesis via RUNX1-GFI1b feedforward control (scRNA-Seq)

Project description:The balance between self-renewal and differentiation of hematopoietic stem cells (HSCs) is orchestrated by the combinatorial function of transcription factors and epigenetic regulators. Here, we report that the H4K16 acetyl-transferase MOF regulates chromatin accessibility and hematopoietic gene expression during erythroid commitment. Mof expression is controlled via a transcriptional feedforward pathway involving Runx1 and Gfi1b, which is crucial for the erythroid lineage bias. Single-cell RNA-seq of HSCs revealed that Mof haploinsufficient mice accumulate an otherwise rare HSC subset, indicating impaired differentiation.We propose that an intricate transcription factor network ensures dynamic chromatin targeting by MOF, which defines an essential epigenetic node regulating HSC plasticity, identity and differentiation. We propose that an intricate transcription factor network ensures dynamic chromatin targeting by MOF, which defines an essential epigenetic node regulating HSC plasticity, identity and differentiation. We propose that an intricate transcription factor network ensures dynamic chromatin targeting by MOF, which defines an essential epigenetic node regulating HSC plasticity, identity and differentiation. We propose that an intricate transcription factor network ensures dynamic chromatin targeting by MOF, which defines an essential epigenetic node regulating HSC plasticity, identity and differentiation.

2020-03-13 | GSE118194 | GEO

MOF directs erythroid fate during hematopoiesis via RUNX1-GFI1b feedforward control (ChIP-Seq)

2020-03-13 | GSE118192 | GEO

A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia [smart-seq2]

Project description:we uncover a key transcriptional network involving hundreds of genes that is required for HSC self-renewal.

2022-11-23 | GSE175520 | GEO