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FOS Guards Quiescence and Potency in Human Hematopoietic Stem Cells [scRNA-seq]

ABSTRACT: Quiescence and limited dividing are critical in preserving potency of hematopoietic stem/progenitor cell (HSPCs) during lifetime, but little is known about how this process is regulated. Here, we show that the mobilized human HSPCs in peripheral blood (PB) are predominantly in a quiescent state, but rapidly exit quiescence and reduce repopulating potency in short-term culture. Through single cell RNA-seq, we identified a panel of regulators highly associated with HSC quiescence exit and cell-cycle entry. These regulators involve different biological processes such as cell-cycle, signaling pathways, metabolisms, etc. Among them, the oncogene, FOS restrains cell-cycle entry and supports repopulating potency in human HSCs through directly binding and regulating genes both for HSC quiescence and potency. Our findings uncover the regulatory program underlying quiescence exit and highlight the critical role of FOS to guard the quiescence and potency in human HSPCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE176272 | GEO | 2021/06/08

REPOSITORIES: GEO

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FOS Guards Quiescence and Potency in Human Hematopoietic Stem Cells [RNA-seq]

Project description:Quiescence and limited dividing are critical in preserving potency of hematopoietic stem/progenitor cell (HSPCs) during lifetime, but little is known about how this process is regulated. Here, we show that the mobilized human HSPCs in peripheral blood (PB) are predominantly in a quiescent state, but rapidly exit quiescence and reduce repopulating potency in short-term culture. Through single cell RNA-seq, we identified a panel of regulators highly associated with HSC quiescence exit and cell-cycle entry. These regulators involve different biological processes such as cell-cycle, signaling pathways, metabolisms, etc. Among them, the oncogene, FOS restrains cell-cycle entry and supports repopulating potency in human HSCs through directly binding and regulating genes both for HSC quiescence and potency. Our findings uncover the regulatory program underlying quiescence exit and highlight the critical role of FOS to guard the quiescence and potency in human HSPCs.

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FOS Guards Quiescence and Potency in Human Hematopoietic Stem Cells [CUT&Tag]

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Attenuation of miR-126 activity expands HSC in vivo without exhaustion

Project description:Life-long blood cell production is governed through the poorly understood integration of cell-intrinsic and -extrinsic control of hematopoietic stem cell (HSC) quiescence and activation. MicroRNAs (miRNAs) coordinately regulate multiple targets within signaling networks making them attractive candidate HSC regulators. We report that miR-126, a miRNA expressed in HSC and early progenitors, plays a pivotal role in restraining cell cycle progression of HSC in vitro and in vivo. miR-126 knockdown using lentiviral sponges increased HSC proliferation without inducing exhaustion, resulting in expansion of mouse and human long-term repopulating HSC. Conversely, enforced miR-126 expression impaired cell cycle entry leading to progressively reduced hematopoietic contribution. In HSC/early progenitors, miR-126 regulates multiple targets within the PI3K/AKT/GSK3β pathway thus attenuating signal transduction in response to extrinsic signals. These data establish that miR-126 sets a threshold for HSC activation and thus governs HSC pool size, demonstrating the importance of miRNA in the control of HSC function. Total RNA was extracted from cord blood Lin- cells and treated with mir126 shRNA or mir126 containing viral particles (and corresponding controls)

2012-11-30 | E-GEOD-40458 | biostudies-arrayexpress

Attenuation of miR-126 activity expands HSC in vivo without exhaustion

2012-11-30 | GSE40458 | GEO

The Greatwall-Endosulfine switch accelerates autophagic flux during the cell divisions leading to G1 arrest and quiescence in fission yeast

Project description:In fission yeast cell cycle exit, autophagy, G1 arrest and entry into quiescence are coordinated by the activity of the protein phosphatase PP2A/B55 through the Greatwall-Endosulfine switch. In order to study the role of this pathway in the transcriptional changes that occur during entry into quiescence, RNA was extracted from wild-type cells and from four mutant strains at three time points.

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Induced cell-autonomous neutropenia systemically perturbs hematopoiesis in Cebpa enhancer-null mice

Project description:Knockouts of the Cebpa gene or its +37kb enhancer in mice show two major findings: (1) neutropenia in bone marrow and blood; (2) decrease in long-term hematopoietic stem cell (LT-HSC) numbers. To study mechanisms linking the two observed events, we applied RNA sequencing on +37kbWT and +37kbHOM bone marrow cells. The analysis of these data revealed that myeloid priming in HSPCs occurs before Cebpa activation and that a neutrophil differentiation block in these progenitors potentially leads to HSC quiescence exit.

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Stationary phase timecourse

Project description:Nine day glucose starvation stationary phase culture, exit and entry from quiescence

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LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells

Project description:Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signalling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence.

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Transcription profiling of mouse Fbw7-/-/hematopoietic stem cells

Project description:Ubiquitination is a post-translational mechanism of control of diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes including Notch1, c-Myc and cyclin E. We have generated conditional Fbw7 knock-out animals and inactivated the gene in hematopoietic stem cells (HSC) and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects the HSC compartment in a cell-autonomous manner. Fbw7-/- HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7-/- HSC are unable to colonize the thymus leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E are stabilized in the bone marrow of Fbw7 deficient mice. Genome-wide transcriptome studies of Fbw7-/- HSC and hematopoietic progenitors indicate that Fbw7 controls, through the regulation of HSC cell cycle entry, the global transcriptional âsignatureâ that is associated with the quiescent, self-renewing HSC phenotype. Transcriptional consequences of inactivating Fbw7 in LKS cells. Experiment Overall Design: Four samples were analyzed: wild-type (WT) control and Fbw7-deficient (FBW7) Lin-ckit+Sca1+ (LSK) cells, as well as Lin-ckit+Sca1- myeloid progenitor (MP) cells, which served as a control for LSK-enriched/specific genes. Total bone marrow cells were pooled from three WT and three FBW7 mice before sorting LSK and MP populations.

2008-06-11 | E-GEOD-11178 | biostudies-arrayexpress

Control of hematopoietic stem cell quiescence by the E3 Ubiquitin Ligase Fbw7

Project description:Ubiquitination is a post-translational mechanism of control of diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes including Notch1, c-Myc and cyclin E. We have generated conditional Fbw7 knock-out animals and inactivated the gene in hematopoietic stem cells (HSC) and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects the HSC compartment in a cell-autonomous manner. Fbw7-/- HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7-/- HSC are unable to colonize the thymus leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E are stabilized in the bone marrow of Fbw7 deficient mice. Genome-wide transcriptome studies of Fbw7-/- HSC and hematopoietic progenitors indicate that Fbw7 controls, through the regulation of HSC cell cycle entry, the global transcriptional “signature” that is associated with the quiescent, self-renewing HSC phenotype. Transcriptional consequences of inactivating Fbw7 in LKS cells. Keywords: cell type comparison

2008-04-15 | GSE11178 | GEO

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