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Ssb1 and Ssb2 have essential and overlapping functions in adult stem cell homeostasis - megakaryocyte-erythroid progenitor data.

ABSTRACT: The single-stranded DNA binding proteins SSB1 and SSB2 are crucial regulators of the DNA damage response, however the overlapping functions of these related proteins is incompletely understood. We generated mice where both Ssb1 and Ssb2 were constitutively or conditionally deleted. Constitutive Ssb1/Ssb2 double knockout (DKO) caused early embryonic lethality, while conditional Ssb1/Ssb2 double knockout (cDKO) in adult mice resulted in acute lethality due to bone marrow failure and intestinal atrophy featured by stem and progenitor cell depletion. cDKO cells exhibited increased replication stress, R-loop accumulation, genome wide double strand breaks and cytosolic single-stranded DNA. Transcriptional profiling of cDKO cells revealed activation of p53 DNA damage and interferon responses. Hematopoietic stem and progenitor cells in cDKO mice showed enforced cell cycling, with subsequent apoptotic cell death. Collectively, these results demonstrate that Ssb1 and Ssb2 have compensatory functions in maintaining genomic stability and are collectively necessary for adult stem cell homeostasis. Single colour, Illumina MouseRef-8 v2.0 Beadarrays.

ORGANISM(S): Mus musculus

SUBMITTER: Glen Boyle

PROVIDER: E-GEOD-75227 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Ssb1 and Ssb2 have essential and overlapping functions in adult stem cell homeostasis - granulocyte-macrophage progenitor data.

Project description:The single-stranded DNA binding proteins SSB1 and SSB2 are crucial regulators of the DNA damage response, however the overlapping functions of these related proteins is incompletely understood. We generated mice where both Ssb1 and Ssb2 were constitutively or conditionally deleted. Constitutive Ssb1/Ssb2 double knockout (DKO) caused early embryonic lethality, while conditional Ssb1/Ssb2 double knockout (cDKO) in adult mice resulted in acute lethality due to bone marrow failure and intestinal atrophy featured by stem and progenitor cell depletion. cDKO cells exhibited increased replication stress, R-loop accumulation, genome wide double strand breaks and cytosolic single-stranded DNA. Transcriptional profiling of cDKO cells revealed activation of p53 DNA damage and interferon responses. Hematopoietic stem and progenitor cells in cDKO mice showed enforced cell cycling, with subsequent apoptotic cell death. Collectively, these results demonstrate that Ssb1 and Ssb2 have compensatory functions in maintaining genomic stability and are collectively necessary for adult stem cell homeostasis. Single colour, Illumina MouseRef-8 v2.0 Beadarrays.

2016-07-03 | E-GEOD-75226 | biostudies-arrayexpress

ASC controls T-bet-dependent CTL differentiation and defines transplant outcome independent of the inflammasome

Project description:The adaptor protein ASC is known to facilitate caspase-1 activation essential for innate host immunity via the formation of the inflammasome complex - a multi-protein structure responsible for processing IL-1beta and IL-18 to their active moieties. Here we demonstrate that ASC-deficient CD8+ T cells fail to induce graft-versus-host disease (GVHD) and have impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects are the result of an inability to differentiate into fully cytolytic, granzyme B-expressing effector cells, with a developmental bias instead towards CD127+KLRG1- memory CD8+ T cells. These alterations in differentiation are inflammasome-independent, since GVHD lethality and CTL differentiation are not altered in recipients of caspase-1-deficient T cells. We demonstrate that ASC binds to T-bet in CD8+ T and in the absence of ASC, the binding of T-bet to the granzyme B promoter is impaired. Thus, the inhibition of ASC represents an attractive therapeutic target to manipulate transplant outcomes. Single colour, Illumina MouseRef-8 v2.0 Beadarrays.

2016-04-01 | E-GEOD-78755 | biostudies-arrayexpress

Ssb1 and Ssb2 have essential and overlapping functions in adult stem cell homeostasis - megakaryocyte-erythroid progenitor data.

2016-01-01 | GSE75227 | GEO

Ssb1 and Ssb2 have essential and overlapping functions in adult stem cell homeostasis - granulocyte-macrophage progenitor data.

2016-01-01 | GSE75226 | GEO

Tc17 cells are a pro-inflammatory, plastic lineage of pathogenic CD8+ T-cells that induce GVHD without anti-leukemic effects

Project description:IL-17-producing cells are important mediators of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Here we demonstrate that a distinct CD8+ Tc17 population develops rapidly after SCT but fails to maintain lineage fidelity such that they are unrecognizable in the absence of a fate reporter. Tc17 differentiation is dependent on alloantigen presentation by host-DC together with IL-6. Tc17 cells express high levels of multiple prototypic lineage-defining transcription factors (e.g. RORgt, T-bet) and cytokines (e.g. IL-17A, IL-22, IFNg, GM-CSF, IL-13). Targeted depletion of Tc17 early after transplant protects from lethal acute GVHD, however Tc17 cells are non-cytolytic and fail to mediate graft–versus–leukemia (GVL) effects. Thus, the Tc17 differentiation program during GVHD culminates in a highly plastic, hyper-inflammatory, poorly-cytolytic effector population which we term inflammatory Tc17 (iTc17). Since iTc17 mediate GVHD without contributing to GVL, therapeutic inhibition of iTc17 development in a clinical setting represents an attractive approach for separating GVHD and GVL. Single colour, Illumina MouseRef-8 v2.0 Beadarrays.

2015-09-13 | E-GEOD-70931 | biostudies-arrayexpress

Modification of T cell responses by stem cell mobilization requires direct signalling of the T cell by G-CSF and IL-10

Project description:The majority of allogeneic stem cell transplants are currently undertaken using G-CSF mobilized peripheral blood stem cells. G-CSF has diverse biological effects on a broad range of cells and IL-10 is a key regulator of many of these effects. Using mixed radiation chimeras in which the haematopoietic or non-haematopoietic compartments were wild-type (WT), IL-10–/–, G-CSFR–/– or combinations thereof we demonstrated that the attenuation of alloreactive T cell responses after with G-CSF mobilization required direct signalling of the T cell by both G-CSF and IL-10. IL-10 was generated principally by radio-resistant tissue, and was not required to be produced by T cells. G-CSF mobilization significantly modulated the transcription profile of CD4+CD25+ regulatory T cells, promoted their expansion in the donor and recipient and their depletion significantly increased graft-versus-host disease (GVHD). In contrast, stem cell mobilization with the CXCR4 antagonist AMD3100 did not alter the donor T cell’s ability to induce acute GVHD. These studies provide an explanation for the effects of G-CSF on T cell function and demonstrate that IL-10 is required to license regulatory function but T cell production of IL-10 is not itself required for the attenuation GVHD. Although administration of CXCR4 antagonists is an efficient means of stem cell mobilization, this fails to evoke the immunomodulatory effects seen during G-CSF mobilization. These data provide a compelling rationale for considering the immunological benefits of G-CSF in selecting mobilization protocols for allogeneic stem cell transplantation. Single colour, Illumina MouseRef-8 v2.0 Beadarrays.

2014-02-03 | E-GEOD-54616 | biostudies-arrayexpress

Ssb1 and Ssb2 have essential and overlapping functions in adult stem cell homeostasis

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-07-03 | E-GEOD-75228 | biostudies-arrayexpress

Proteomic analysis of DNA synthesis on a structured DNA template in human cellular extracts: Interplay between NHEJ and replication-associated proteins

Project description:It has been established that short inverted repeats (SIRs) trigger base substitution mutagenesis in human cells. However, how the replication machinery deals with this structured DNA is unknown. We have previously reported that in human cell-free extracts, DNA primer extension using a structured single-stranded DNA template is transiently blocked at DNA hairpins [1](Schmutz et al., 2007). Here, we report the proteomic analysis of proteins bound to the DNA template providing evidence that proteins of the NHEJ pathway, particularly the DNA-PK complex (composed of DNA-PKcs and the Ku70/Ku80 dimer) recognize structured single-stranded DNA. DNA-PKcs inhibition results in the mobilization on the template DNA of the DNA-PK complex, along with other proteins acting downstream in the NHEJ pathway, especially the XRCC4-DNA Ligase 4 complex and the recently identified cofactor PAXX. The retention of NHEJ factors to the template DNA in the absence of DNA-PKcs activity correlates with additional halts of primer extension, suggesting that NHEJ proteins may hinder the progression of the DNA synthesis at these sites. Conversely, hijacking of the DNA-PK complex by double-stranded oligos (dsO) results in a large removal of the pausing sites and an elevated DNA extension efficiency. Overall these results raise the possibility that, upon binding to DNA hairpins formed onto ssDNA during fork progression, the DNA-PK complex may play some role in replication fork dynamics in vivo, role that is however not related to repair of double-strand breaks.

2020-02-04 | PXD011156 | Pride

Effect of Oral Administration of Methylene Blue MMX Tablets on Double Stranded DNA

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| 2178654 | ecrin-mdr-crc

Microarray expression profiling of the Igf2 pathway dependency of Trp53 developmental and tumour phenotypes in mice

Project description:We tested whether loss of p53 function leads to insulin-like growth factor 2 (IGF2) pathway dependency in vivo in genetically defined mouse models. Unexpectedly we found lethality, due to post-natal lung haemorrhage, occurred in Igf2 paternal null allele female mice (Igf2-p) but only if derived from double heterozygote fathers (Igf2-p, p53+/-). Consequently we investigated the effects of paternal genotype (wild-type, Igf2-p and Igf2-p, p53+/-) on gene expression. Microarray gene expression profiling of whole mouse embryos (embryonic day 9.5) revealed that lethality was associated with a specific gene signature. Since double heterozygote female offspring (Igf2-p, p53+/-) of Igf2-p, p53+/- fathers did not have the lethality phenotype we identified gene expression changes associated with this 'rescue'. Supplementary information available when browsing all available files.

2012-06-01 | E-MTAB-1001 | biostudies-arrayexpress

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