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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.

ORGANISM(S): Mus musculus

PROVIDER: GSE70658 | GEO | 2015/07/10

SECONDARY ACCESSION(S): PRJNA289307

REPOSITORIES: GEO

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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. 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.

2015-07-10 | E-GEOD-70658 | 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

Oval cells from DDB1 mutant mouse

2012-01-01 | GSE31588 | GEO

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

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 | 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

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

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Mitochondrial respiratory chain is essential for hematopoietic stem cell function

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2017-09-13 | PXD006054 | Pride

Structure of the DDB1-AMBRA1 E3 ligase receptor complex linked to cell cycle regulation

Project description:AMBRA1 is a tumor suppressor protein that functions as a substrate receptor of the ubiquitin conjugation system with roles in autophagy and the cell cycle regulatory network. The intrinsic disorder of AMBRA1 has thus far precluded its structural determination. To solve this problem, we analyzed the dynamics of AMBRA1 using hydrogen deuterium exchange mass spectrometry (HDX-MS). The HDX results indicated that AMBRA1 is a highly flexible protein and can be stabilized upon interaction with DDB1, the adaptor of the Cullin4A/B E3 ligase. Here, we present the cryo-EM structure of AMBRA1 in complex with DDB1 at 3.08 Å resolution. The structure shows that parts of the N- and C-terminal structural regions in AMBRA1 fold together into the highly dynamic WD40 domain and reveals how DDB1 engages with AMBRA1 to create a binding scaffold for substrate recruitment. The N-terminal helix-loop-helix motif and WD40 domain of AMBRA1 associate with the double-propeller fold of DDB1. We also demonstrate that DDB1 binding-defective AMBRA1 mutants prevent ubiquitination of the substrate Cyclin D1 in vitro and increase cell cycle progression. Together, these results provide structural insights into the AMBRA1-ubiquitin ligase complex and suggest a mechanism by which AMBRA1 acts as a hub involved in various physiological processes.

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Igf2bp2 deletion reduces energy metabolism, gIgf2bp2 deletion reduces energy metabolism, growth signaling, and aging of hematopoietic stem cells in micerowth signaling, and aging of hematopoietic stem cells in mice

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