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RNA-sequencing analysis of adult mouse wild type (Prdm16-Mx1-Cko/Cko; +/+) and Prdm16-/- (Prdm16-Mx1-Cko/Cko; Tg/+) Long Term-Hematopoietic Stem Cells (LT-HSC).

ABSTRACT: Regulation of quiescence is critical for the maintenance of adult hematopoietic stem cells (HSCs). Previous studies by gene disruption during mouse embryonic development have shown that transcription factor gene Prdm16 is important for the generation/maintenance of fetal liver HSCs; however, the underlying mechanisms and the function of Prdm16 in adult HSCs remain unclear. To investigate the role of Prdm16 in adult HSCs, we generated a novel conditional knockout mouse model and deleted Prdm16 in adult mouse hematopoietic system using the interferon inducible Mx1-Cre. Our results show that deletion of Prdm16 leads to a gradual decline of adult HSC numbers and a concomitant increase in the multipotent progenitor (MPP) compartment. Prdm16 deletion in the hematopoietic system following transplantation produced the same phenotype indicating that the defect is intrinsic to the HSCs. This HSC loss was also exacerbated by stress induced by 5-FU injections. Annexin V staining showed no difference in apoptosis between wild type and knockout HSCs. In contrast, BrdU analysis revealed that loss of Prdm16 significantly increases cycling of long-term HSCs (LT-HSCs) with majority of the cells found in the S to G2/M phase. Consistently, RNA-seq analysis of mouse LT- HSCs with and without Prdm16 deletion showed that Prdm16 loss induced a significant decrease in the expression of several known cell cycle regulators of HSCs, among which Cdkn1a and Egr1 were further identified as direct targets of Prdm16. Our results suggest that Prdm16 preserves the function of adult LT-HSCs by promoting their quiescence.

ORGANISM(S): Mus musculus

PROVIDER: GSE154011 | GEO | 2021/11/22

REPOSITORIES: GEO

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RNA-sequencing analysis of adult mouse wild type (Prdm16-Mx1-Cko/Cko; +/+) and Prdm16-/- (Prdm16-Mx1-Cko/Cko; Tg/+) Long Term-Hematopoietic Stem Cells (LT-HSC).

Project description:RNA-sequencing analysis of adult mouse wild type (Prdm16-Mx1-Cko/Cko; +/+) and Prdm16-/- (Prdm16-Mx1-Cko/Cko; Tg/+) Long Term-Hematopoietic Stem Cells (LT-HSC).

| PRJNA644817 | ENA

mRNA expression of murine hematopoietic stem cells and ex vivo murine MLL-AF9 cells deficient for total PRDM16 or f-PRDM16, and AF9 cells overexpressing individual PRDM16 isoforms

Project description:Group 1 -- WT or PRDM16-KO ex vivo murine MLL-AF9 cells, and PRDM16-KO AF9 cells overexpressing either f-PRDM16 or s-PRDM16. Group 2 -- WT or total PRDM16-KO murine HSCs isolated from adult BM. Group 3 -- WT or total PRDM16-KO murine HSCs isolated from fetal liver. Group 4 -- WT or f-PRDM16-KO murine HSCs (expressing s-PRDM16 only) isolated from fetal liver.

2018-06-08 | GSE112860 | GEO

Transcription profiling of mouse long term HSC from control or Pbx1-null mice

Project description:Self-renewal is a defining characteristic of stem cells, however the molecular pathways underlying its regulation are poorly understood. Here we demonstrate that conditional inactivation of the Pbx1 proto-oncogene in the hematopoietic compartment results in a progressive loss of long-term hematopoietic stem cells (LT-HSCs) that is associated with concomitant reduction in their quiescence, leading to a defect in the maintenance of self-renewal as assessed by serial transplantation. Transcriptional profiling revealed that multiple stem cell maintenance factors are perturbed in Pbx1-deficient LT-HSCs, which prematurely express a large subset of genes, including cell cycle regulators, normally expressed in non-self-renewing multipotent progenitors. A significant proportion of Pbx1-dependent genes are associated with the Tgf-b pathway, which serves a major role in maintaining HSC quiescence. Pbx1-deficient LT-HSCs are unable to up-regulate the cyclin dependent kinase inhibitor p57 in response to Tgf-b, providing a mechanism through which Pbx1 maintenance of stem cell self-renewal is achieved. Experiment Overall Design: Highly efficient Pbx1 deletion was induced with poly(I:C) in 3 young MxCre+.Pbx1f/f mutant or 2 MxCre-.Pbx1f/f control mice. LT-HSC (Lin-cKit+Sca1+CD34-CD135-) cells were prospectively sorted from bone marrow of individual mice harvested 4 weeks after the last injection of poly(I:C).

2008-06-20 | E-GEOD-9188 | biostudies-arrayexpress

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

Neogenin-1 distinguishes between myeloid-biased and balanced Hoxb5+ mouse long-term hematopoietic stem cells

Project description:Hematopoietic stem cells (HSCs) self-renew and generate all blood cells. Recent studies with single-cell transplants and lineage tracing suggest that adult HSCs are diverse in their reconstitution and lineage potentials. However, prospective isolation of these subpopulations has remained challenging. Here, we identify Neogenin-1 (NEO1) as a unique surface marker on a fraction of mouse HSCs labeled with Hoxb5, a specific reporter of long-term HSCs (LT-HSCs). We show that NEO1+Hoxb5+ LT-HSCs expand with age and respond to myeloablative stress in young mice, while NEO1–Hoxb5+ LT-HSCs exhibit no significant change in number. Furthermore, NEO1+Hoxb5+ LT-HSCs are more often in the G2/S cell cycle phase compared to NEO1–Hoxb5+ LT-HSCs in both young and old bone marrow. Upon serial transplantation, NEO1+Hoxb5+ LT-HSCs exhibit myeloid-biased differentiation and reduced reconstitution, while NEO1–Hoxb5+ LT-HSCs are lineage-balanced and stably reconstitute recipients. Gene expression analysis reveals erythroid and myeloid priming in the NEO1+ fraction and association of quiescence and self-renewal-related transcription factors with NEO1− LT-HSCs. Finally, transplanted NEO1+Hoxb5+ LT-HSCs rarely generate NEO1–Hoxb5+ LT-HSCs, while NEO1–Hoxb5+ LT-HSCs repopulate both LT-HSC fractions. This supports a model in which dormant, balanced, NEO1–Hoxb5+ LT-HSCs can hierarchically precede active, myeloid-biased NEO1+Hoxb5+ LT-HSCs.

2019-11-10 | GSE130504 | GEO

PRDM16 ChIP-Seq in Prdm16 WT and KO duodenal crypts

Project description:PRDM16 ChIP was perfomed in control and Prdm16 KO crypts isolated from the duodenum of 6 week old mice 3 days after inducible gene deletion

2020-02-26 | GSE131487 | GEO

RNA-Seq of E14 MGE, Prdm16 WT vs cKO

Project description:This study aimed to understand the role of the transcriptional regulator Prdm16 in the development of cortical interneurons in the mouse. Prdm16 was knocked out in cells derived from the medial ganglionic eminence (MGE) by using an Nkx2.1-Cre driver line in combination with a line carrying floxed Prdm16 alleles and with a Cre-dependent tdTomato reporter line (Ai14). The sequencing data compares the gene expression profiles of dissected MGEs at embryonic day 14 (E14), a stage when cortical interneurons are being generated from MGE progenitors.

2020-10-22 | GSE159728 | GEO

Regulatory Role of S100A6 in Hematopoetic Stem Cells

Project description:The fate options of hematopoietic stem cells (HSCs) include self-renewal, differentiation, migration and apoptosis, but the interaction between intracellular Ca2+ and cytoplasmic chaperon protein in regulating fate options of long term-HSCs (LT-HSC) is unknown. We created a S100A6 conditional knockout mouse model in the hematopoietic system and our studies showed that in S100A6KO, the number of LT-HSCs was significantly reduced and HSCs engrafted poorly. After 5FU challenge, the frequency of S100A6KO HSCs remained significantly low. Our data showed that S100A6 failed to self-renew through Akt pathway in an intracellular calcium (Cai2+)-dependent manner. Expression profiling of S100A6KO obtained from gene signatures revealed that cytosolic calcium level and proteins translocation to mitochondria were decreased. Mitochondrial oxidative phosphorylation was impaired in S100A6KO. Proteomic data indicated Hsp90 protein and chaperonin family were reduced. Our findings demonstrated that S100A6 regulates fate options of HSCs self-renewal through integrating Akt signaling, specifically governing mitochondria metabolic function and protein quality.

2020-06-22 | PXD015854 | Pride

RNA-seq in Prdm16 KO duodenal crypts

Project description:The adult intestinal epithelium is maintained by a continuous replacement of differentiated cells from stem cells. Previous studies suggest that cellular metabolic pathways regulate intestinal stem cell activity and differentiation. However, little is known about the cell-intrinsic factors that control these metabolic programs. Here, we identify the transcription factor PRDM16 as a critical regulator of intestinal metabolic programing and stem cell differentiation. Acute deletion of Prdm16 in adult mice causes severe intestinal wasting, apoptosis, and an accumulation of poorly differentiated cells in the crypt. Prdm16-deficient crypts display decreased expression levels of fatty acid oxidation (FAO) genes and reduced rates of FAO. PRDM16 binds, along with its protein partners PPARγ and PPARα, to the promoter and enhancer regions of many FAO genes. The loss of Prdm16 or inhibition of FAO impaired the transition of intestinal stem cells into transit amplifying cells. Notably, PRDM16 expression is highest in the duodenum and declines distally along the intestine. This gradient of PRDM16 expression controls the region-specific expression of the FAO program and underlies the differential reliance of region-specific stem cells on FAO. Altogether, this study establishes PRDM16 as a regional-specific regulator of metabolism and stem cell differentiation in the intestine.

2020-02-26 | GSE121009 | GEO

H3K27Ac ChIP-Seq in Prdm16 KO duodenal crypts

Project description:The adult intestinal epithelium is maintained by a continuous replacement of differentiated cells from stem cells. Previous studies suggest that cellular metabolic pathways regulate intestinal stem cell activity and differentiation. However, little is known about the cell-intrinsic factors that control these metabolic programs. Here, we identify the transcription factor PRDM16 as a critical regulator of intestinal metabolic programing and stem cell differentiation. Acute deletion of Prdm16 in adult mice causes severe intestinal wasting, apoptosis, and an accumulation of poorly differentiated cells in the crypt. Prdm16-deficient crypts display decreased expression levels of fatty acid oxidation (FAO) genes and reduced rates of FAO. PRDM16 binds, along with its protein partners PPAR? and PPAR?, to the promoter and enhancer regions of many FAO genes. The loss of Prdm16 or inhibition of FAO impaired the transition of intestinal stem cells into transit amplifying cells. Notably, PRDM16 expression is highest in the duodenum and declines distally along the intestine. This gradient of PRDM16 expression controls the region-specific expression of the FAO program and underlies the differential reliance of region-specific stem cells on FAO. Altogether, this study establishes PRDM16 as a regional-specific regulator of metabolism and stem cell differentiation in the intestine.

2020-02-26 | GSE120897 | GEO

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