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The E3 ubiquitin ligase DDB1 controls homeostasis of hematopoietic stem and progenitor cells

ABSTRACT: Hematopoietic stem cells (HSC) are regulated to keep the balance between self-renewal and differentiation. However, little is known about post-translational regulations in HSCs. In this study, we characterize the role of DDB1, a component of the Cul4A-DDB1 E3 ubiquitin ligase complex, in HSCs and progenitors by using conditional DDB1 knockout models. We show that the maintenance and differentiation of both adult and fetal HSCs and progenitor cells is dependent on DDB1 function. Deletion of DDB1 alters cell cycle progression and induces apoptosis. Furthermore, deletion of DDB1 in developing thymocytes had no effects on T cell differentiation, whereas DDB1-deficient peripheral T cells were not able to enter cell cycle when stimulated in vitro. In addition, DDB1 is essential for T cell leukemia initiation. Our results reveal that DDB1 is required for adult and fetal hematopoiesis as it controls progenitor and stem cell homeostasis. Transcriptional consequences of inactivating DDB1 in fetal LSK cells. Four samples were analyzed: wild-type (WT) control and DDB1-deficient (DDB1) Lin-ckit+Sca1+ (LSK) cells sorted from fetal livers E16.5 of DDB1 flox/flox, VavCre+ and control mice.

ORGANISM(S): Mus musculus

SUBMITTER: Shannon buckley

PROVIDER: E-GEOD-70658 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The E3 ubiquitin ligase DDB1 controls homeostasis of hematopoietic stem and progenitor cells

Project description:Hematopoietic stem cells (HSC) are regulated to keep the balance between self-renewal and differentiation. However, little is known about post-translational regulations in HSCs. In this study, we characterize the role of DDB1, a component of the Cul4A-DDB1 E3 ubiquitin ligase complex, in HSCs and progenitors by using conditional DDB1 knockout models. We show that the maintenance and differentiation of both adult and fetal HSCs and progenitor cells is dependent on DDB1 function. Deletion of DDB1 alters cell cycle progression and induces apoptosis. Furthermore, deletion of DDB1 in developing thymocytes had no effects on T cell differentiation, whereas DDB1-deficient peripheral T cells were not able to enter cell cycle when stimulated in vitro. In addition, DDB1 is essential for T cell leukemia initiation. Our results reveal that DDB1 is required for adult and fetal hematopoiesis as it controls progenitor and stem cell homeostasis. Transcriptional consequences of inactivating DDB1 in fetal LSK cells.

2015-07-10 | GSE70658 | GEO

DDB1 Binds Histone Reader BRWD3 to Activate the Transcriptional Cascade in Adipogenesis and Promote Onset of Obesity (ChIP-seq II)

Project description:DDB1 is typically recognized as a component of the Cullin4 (CUL4)-RING E3 ubiquitin ligase complex. Here, we show that DDB1 functions independently of CUL4 to promote adipogenesis and diet-induced obesity. In contrast to depletion of CUL4A or CUL4B that stimulates adipogenesis, lack of DDB1 dramatically suppresses the process. Re-introduction of a DDB1 mutant that lacks the binding ability to CUL4A or CUL4B fully restores adipogenesis in DDB1-deficient preadipocytes. Furthermore, while inducibly knocking out Cul4a or Cul4b in mice aggravates diet-induced obesity, Ddb1+/- mice are lean on high-fat diet. Mechanistically, by binding the bromodomain-containing histone reader BRWD3, DDB1 is recruited to acetylated histones in the proximal promoters of immediate-early response genes, where it facilitates the release of paused RNA polymerase II (Pol II) and activates the transcription of these genes. Our findings have thus uncovered a mechanism of activating the transcriptional cascade in adipogenesis by DDB1-mediated release of paused Pol II.

2023-09-17 | GSE168136 | GEO

DDB1 Binds Histone Reader BRWD3 to Activate the Transcriptional Cascade in Adipogenesis and Promote Onset of Obesity (RNA-Seq)

2023-09-17 | GSE158172 | GEO

DDB1 Binds Histone Reader BRWD3 to Activate the Transcriptional Cascade in Adipogenesis and Promote Onset of Obesity (ChIP-Seq)

2023-09-17 | GSE158171 | GEO

Retroviral Sox17 over-expression adult hematopoietic stem/progenitor cells microarray

Project description:The transcription factor SOX17 is expressed by fetal, but not adult hematoipoietic stem cells (HSCs), and is required for the maintenance of fetal and neonatal, but not adult, HSCs. In the current study we show that ectopic expression of Sox17 in adult HSCs and transiently reconstituting multipotent progenitors was sufficient to confer increased self-renewal potential and the expression of fetal HSC genes including fetal HSC surface markers. To assess the mechanisms by which ectopic Sox17 expression in adult hematopoietic progenitors increased self-renewal potential and conferred fetal HSC properties, we compared the gene expression profiles of E16.5 fetal liver HSCs, young adult bone marrow HSCs, young adult bone marrow CD48+LSK cells, and Sox17-expressing CD48+LSK cells isolated from mice that had been transplanted with MSCV-Sox17-infected bone marrow cells 12 weeks earlier. Total RNA (~5ng) was isolated from 3 independent, freshly isolated aliquots of 10,000 E16.5 fetal liver HSCs, 10,000 fetal liver CD48+LSK cells, 10,000 adult bone marrow HSCs, 10,000 adult bone marrow CD48+LSK cells, 10,000 Sox17-expressing CD48+LSK cells isolated from primary recipients 12 weeks after transplantation of MSCV-Sox17-infected bone marrow cells. Purified RNA was reverse transcribed and amplified using the WT-Ovation™ Pico RNA Amplification system (NuGEN Technologies) following the manufacturer’s instructions. Sense strand cDNA was generated using WT-Ovation™ Exon Module (NuGEN), then fragmented and labeled using the FL-Ovation™ cDNA Biotin Module V2 (NuGEN). 2.5µg of labeled cDNA were hybridized to Affymetrix Mouse Gene ST 1.0 microarrays.

2011-07-14 | E-GEOD-30444 | biostudies-arrayexpress

Expression data from control and LRF (leukemia/lymphoma related factor)-deficient mouse LT-HSCs

Project description:LRF, which is encoded by the ZBTB7A gene and formerly known as POKEMON (POK erythroid myeloid ontogenic factor), was originally identified as a PLZF (promyelocytic leukemia zinc finger) homologue interacting with BCL6 (B-cell lymphoma 6). LRF is a transcription factor that is broadly expressed in hematopoietic lineage cells, but its expression is particularly high in erythroblasts and germinal center (GC) B-cells. The goal of this study is to assess the effect of LRF loss on the LT-HSC transcriptome. Nine days after injection of adult mice with polyinosinic polycytidylic acid (pIpc) to activate Cre, total RNAs were isolated from double-sorted LT-HSCs from LRF Flox/+ Mx1-Cre+ and LRF Flox/Flox Mx1-Cre+ mice and processed for microarray analysis. We performed gene expression microarray analysis of FACS-sorted LT-HSCs (LSK IL7Ra-Flt3-CD150+CD48-) to assess the effect of Lrf loss on the LT-HSC transcriptome. Zbtb7a Flox/+ Mx1-Cre+ mice were used as a control to normalize the potential effects of Cre recombinase. LT-HSCs were FACS-sorted from three Lrf knockout (Zbtb7a Flox/Flox Mx1-Cre+) and two control (Zbtb7a Flox/+ Mx1-Cre+) mice, nine days after the first pIpC injection.

2012-10-26 | E-GEOD-41839 | biostudies-arrayexpress

Oval cells from DDB1 mutant mouse

Project description:Quiescent hepatic stem cells (HSCs) can be activated when hepatocyte proliferation is compromised. Chemical injury rodent models have been widely used to study the locazation, biomarkers, and signaling pathways in HSCs, but these models usually exhibit severe promiscuous toxicity and fail to distinguish damaged and non-damaged cells. Our goal is to establish new animal models to overcome these limitations, thereby providing new insights into HSC biology and application. We generated mutant mice with constitutive or inducible deletion of Damaged DNA Binding protein 1 (DDB1), an E3 ubiquitin ligase, in hepatocytes. We show that deletion of DDB1 abolishes self-renewal capacity of mouse hepatocytes in vivo, leading to compensatory activation and proliferation of DDB1-expressing OCs. Importantly, the DDB1 mutant mice exhibit very minor liver damage, compared to a chemical injury model. Microarray analysis reveals several previously unrecognized markers, enriched in oval cells. This genetic model in which irreversible inhibition of hepatocyte duplication results in HSC-driven liver regeneration. The DDB1 mutant mice can be broadly applied to studies of HSC differentiation, HSC niche and HSCs as origin of liver cancer. Total RNA obtained from isolated EpCAM+ cells from DDB1 mutant mice compared to wild type hepatocytes

2012-01-01 | E-GEOD-31588 | biostudies-arrayexpress

Retroviral Sox17 over-expression adult hematopoietic stem/progenitor cells microarray

2011-07-15 | GSE30444 | GEO

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

Transcriptomic analysis of HSC-enriched population from adult C57Bl6 bone marrow

Project description:HSC-enriched LSK CD150+CD48- and Lin+ hematopoietic populations were sorted from C57Bl6 adult bone marrow. Their transcriptome was established, and pair-wise comparison performed to establish molecular signatures specific of adult HSCs that could be compared to molecular signatures from AGM, fetal liver or placenta HSCs.

2019-08-24 | GSE133812 | GEO

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