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RNA-seq analysis in RISP WT and KO hematopoietic stem cells

ABSTRACT: Adult and fetal hematopoietic stem cells (HSCs) display a glycolytic phenotype required to maintain stem cell properties; 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), encoded by the Uqcrfs1 gene, in fetal mouse HSCs, results in anemia and prenatal death. RISP null fetal HSCs displayed impaired respiration, resulting in a decreased NAD+/NADH ratio and an increase in glycolysis. While they were viable and able to robustly proliferate in vivo, RISP null fetal HSCs had impaired differentiation, resulting in a depletion of the progenitor pool. RNA-seq analysis revealed widespread changes in gene expression due to loss of RISP in fetal HSCs. Furthermore, 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 a decreased NAD+/NADH ratio, increased glycolysis and loss of quiescence, followed by rapid depletion resulting in severe pancytopenia and lethality. The effect of RISP ablation in fetal or adult HSCs was cell-autonomous. Together, these data indicate that respiration is dispensable for HSC proliferation, but essential for HSC differentiation and maintenance of adult HSC quiescence.

ORGANISM(S): Mus musculus

PROVIDER: GSE95341 | GEO | 2017/05/15

SECONDARY ACCESSION(S): PRJNA376700

REPOSITORIES: GEO

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Project description:Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive and non-supportive stromal clones established from the AGM, FL and BM. Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive line from Fetal Calvaria (OP9) and non-supportive stromal clones from fetal liver (BFC). Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive and non-supportive stromal clones established from fetal liver. We took advantage of stromal clones established from the AGM, FL and BM and tested for their ability to support or not HSCs ex vivo. RNA were extracted from confluent stromal cultures or sorted cells and used for hybridization of Affymetrix (mouse gene 1.0 ST) microarrays.

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RNA-seq analysis in RISP WT and KO hematopoietic stem cells

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