Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA205522 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The DNA-dependent protein kinase (DNA-PK), composed of the KU heterodimer and the catalytic subunit (DNA-PKcs), is a classical non-homologous end-joining (cNHEJ) factor1. KU binds to DNA ends, initiates cNHEJ, and recruits and activates DNA-PKcs. Beyond DNA, KU also binds to RNA, with unknown significance in mammals. Using mouse models, we uncovered an unexpected role for DNA-PK in ribosomal RNA (rRNA) biogenesis and hematopoiesis. Expression of kinase-dead (KD) DNA-PKcs (DNA-PKcsKD/KD) abroagates cNHEJ2. But DNA-PKcsKD/KDTp53-/- mice develop myeloid disease rather than pro-B cell lymphoma, like other cNHEJ/Tp53-deficient mice3. DNA-PKcs is its own the best substrate. Blocking DNA-PKcs phosphorylation at the T2609, but not the S2056 cluster leads to KU-dependent 18S rRNA processing defects, compromises global protein synthesis in hematopoietic cells and causes bone marrow failure in mice. KU drives assembly of DNA-PKcs on a broad array of cellular RNAs, including the U3 small nucleolar RNA (snoRNA), which is essential for 18S rRNA processing4. U3 activates purified DNA-PK and triggers T2609 phosphorylation. DNA-PK, but not other cNHEJ factors, resides in nucleoli in an rRNA-dependent manner and is co-purified with the small subunit (SSU) processome. Together our data show that DNA-PK has RNA-dependent, but cNHEJ-independent, functions during ribosome biogenesis that require DNA-PKcs’ kinase activity and T2609 cluster’s phosphorylation.
2020-01-05 | GSE109026 | GEO
Project description:Fibro adipogenic progenitors (FAPs) promote satellite cell differentiation in adult skeletal muscle regeneration. However, in pathological conditions, FAPs are responsible for fibrosis and fatty infiltrations. Here we show that the NOTCH pathway negatively modulates FAP differentiation both in vitro and in vivo. However, FAPs isolated from young dystrophin- deficient mdx mice are insensitive to this control mechanism. An unbiased mass spectrometry-based proteomic analysis of FAPs from muscles of wild type and mdx mice, suggest that the synergistic cooperation between NOTCH and inflammatory signals controls FAP differentiation. Remarkably, we demonstrated that factors released by hematopoietic cells restore the sensitivity to NOTCH adipogenic inhibition in mdx FAPs. These results offer a basis for rationalizing pathological ectopic fat infiltrations in skeletal muscle and may suggest new therapeutic strategies to mitigate the detrimental effects of fat depositions in muscles of dystrophic patients.
2019-06-24 | PXD014195 | Pride
Project description:Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and increased risk for myelodysplasia and leukemia. Deficient DNA repair contributes to the decline in HSC self-renewal capacity during aging and it remains unclear whether extrinsic signals can rejuvenate aged HSCs. Here, we demonstrate that augmentation of non-homologous end-joining (NHEJ) DNA repair in aged HSCs via treatment with epidermal growth factor (EGF) rejuvenates HSC function. Seven day culture of BM CD34-ckit+sca-1+lin- (34-KSL) HSCs from aged C57BL/6 mice with EGF suppressed myeloid skewing and increased production of multipotent CFU-granulocyte, erythroid, monocyte and megakaryocyte (CFU-GEMM) colonies. Aged, EGF-treated HSCs displayed increased donor multilineage engraftment in primary competitively transplanted mice and in secondary mice compared to mice transplanted with aged, control HSCs. Donor cell engraftment within the bone marrow (BM) KSL and SLAM+KSL HSC population was > 2-fold increased in mice transplanted with aged, EGF-treated HSCs. Systemic administration of EGF to aged mice for 6 weeks also increased long term – HSC self-renewal capacity as measured by increased donor bone marrow (BM) competitive repopulation in primary and secondary transplanted mice. Conversely, deletion of EGFR in Scl/Tal1+ hematopoietic cells was associated with increased myeloid skewing and depletion of LT-HSCs in middle aged mice. Mechanistically, EGF treatment decreased DNA damage in aged HSCs through activation of DNA PK-cs, Artemis and NHEJ repair. Inhibition of DNA PK-cs blocked EGF-mediated restoration of multipotent differentiation and suppression of myeloid skewing in aged HSCs, suggesting that the restoration of hematopoietic potential in aged HSCs is dependent on EGF-mediated activation of DNA PK-cs. EGF treatment also converted the transcriptome of aged HSCs from enrichment for genes involved in cell death and survival to genes involved in HSC generation and identity. These data suggest that extrinsic activation of EGFR signaling can restore key functional capacities in aged HSCs.
2024-04-01 | GSE252293 | GEO
Project description:Transgenic expression of TLX1 induces T-cell leukemias in mice. We used microarrays to identify the gene expression signatures associated with TLX1 tumors compared with different genetic models T acute lymphoblastic lymphoma.
2010-10-19 | GSE19499 | GEO
Project description:Collombet2016 - Lymphoid and myeloid cell
specification and transdifferentiation
This model is described in the article:
Logical modeling of lymphoid
and myeloid cell specification and transdifferentiation
Samuel Collombet, Chris van Oevelen,
Jose Luis Sardina Ortega, Wassim Abou-Jaoudé, Bruno Di
Stefano, Morgane Thomas-Chollier, Thomas Graf, and Denis
Thieffry
Proceedings of the National Academy of
Sciences of the United States of America
Abstract:
Blood cells are derived from a common set of hematopoietic
stem cells, which differentiate into more specific progenitors
of the myeloid and lymphoid lineages, ultimately leading to
differentiated cells. This developmental process is controlled
by a complex regulatory network involving cytokines and their
receptors, transcription factors, and chromatin remodelers.
Using public data and data from our own molecular genetic
experiments (quantitative PCR, Western blot, EMSA) or
genome-wide assays (RNA-sequencing, ChIP-sequencing), we have
assembled a comprehensive regulatory network encompassing the
main transcription factors and signaling components involved in
myeloid and lymphoid development. Focusing on B-cell and
macrophage development, we defined a qualitative dynamical
model recapitulating cytokine-induced differentiation of common
progenitors, the effect of various reported gene knockdowns,
and the reprogramming of pre-B cells into macrophages induced
by the ectopic expression of specific transcription factors.
The resulting network model can be used as a template for the
integration of new hematopoietic differentiation and
transdifferentiation data to foster our understanding of
lymphoid/myeloid cell-fate decisions.
This model is hosted on
BioModels Database
and identified by:
MODEL1610240000.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-06-08 | MODEL1610240000 | BioModels
Project description:DNA methylation data from mouse hematopoietic progenitors
| PRJNA131495 | ENA
Project description:Tcf1 is necessary for optimal T lineage development. Tcf1 deficient progenitors fail to initiate the T lineage program in vitro and development is severely defective in vivo. We used microarrays to assess the overal global gene expression differences from Tcf1 wildtype and deficient lymphoid biased progenitors cultures on Notch-ligand expressing stroma to determine if Tcf1 deficient progenitors are able to intiate the T lineage specification program. Abstract of manuscript: The thymus imposes the T cell fate on incoming multipotent progenitors, but the molecular mechanisms are poorly understood. We show that transcription factor Tcf1 initiates T-lineage-specific gene expression. Tcf1 is downstream of Notch1 signaling and expressed in early T-cell progenitors. Progenitors deficient for Tcf1 are unable to initiate normal T-lineage specification. Conversely, ectopic expression of Tcf1 in hematopoietic progenitors is sufficient to induce expression of T-lineage specific genes in vitro. Thus, our study identifies Tcf1 as critically involved in the establishment T cell identity. Tcf1 wildtype and deficient bone marrow lymphoid primed progenitors (LMPPs, Lineage marker- Sca+kit+Flt3high) were harvested in triplicate and seeded onto OP9-DL4 expressing stroma for 4 days upon which highly pure lineage negative and Thy1+CD25+ T cells were cell sorted for expression analysis. The lineage negative populations represent three seperate mice from each genotype and the Thy1+CD25+T lineage population represents two replicates from the Tcf1 wildtype group. No Thy1+CD25+ T lineage cells develop from Tcf1 deficient progentiors.
2011-08-03 | E-GEOD-26559 | biostudies-arrayexpress
Project description:The noncluster homeodomain containing gene, HOX11/TLX1 (TLX1) is detected at the breakpoint of the t(10;14)(q24;q11) chromosome translocation in patients with T cell Acute Lymphoblastic leukemia (T-ALL). This translocation results in the inappropriate expression of TLX1 in T cells. The oncogenic potential of TLX1 was demonstrated in IgHµ-TLX1Tg mice, which developed mature B cell lymphoma after a long latency period suggesting the requirement of additional mutations to initiate malignancy. To determine whether dysregulation of genes involved in the DNA damage response contributed to tumor progression, we crossed IgHµ-TLX1Tg mice with PrkdcScid/Scid mice; To identify the molecular pathways dysregulated in the earliest stages of TLX1-induced transformation, we used Affimetrix microarrays to compare gene expression profiling of premaliganant thymocytes (6~8 weeks old): DN1, DN2 and DN3 stages from HOX11 transgenic PrkdcScid/Scid (HOXSCID) mice with the same stage thymocytes from the sex and age matched control PrkdcScid/Scid (SCID) mice. Expression analysis of IgH-TLX1TgPrkdcScid/Scid thymocytes revealed dysregulated expression of cell cycle, apoptotic, mitotic spindle and anaphase-promoting complex genes in double negative (DN) 2 and DN3 stage thymocytes. Moreover, DN1, DN2 and DN3 TLX1-expressing thymocytes showed downregulated expression of ribosomal and mitochondria ribosomal protein genes.
2014-04-05 | GSE47421 | GEO
Project description:The T-cell leukemia homeobox 1 (TLX1, HOX11) transcription factor is critically involved in the multistep pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and often cooperates with NOTCH1 activation during malignant T-cell transformation. However, the exact molecular mechanisms by which these T-cell specific oncogenes cooperate during transformation remain to be established. Here, we used an integrative genomics approach to show that the oncogenic properties of TLX1 are mediated by genome-wide interference with the ETS1 and RUNX1 transcription factors. Partial disruption of ETS1 and RUNX1 activity by ectopic TLX1 expression in immature thymocytes drives repression of T-cell specific super-enhancers and mediates an unexpected transcriptional antagonism with NOTCH1 signaling. These phenomena coordinately trigger a TLX1 driven pre-leukemic phenotype in human thymic precursor cells, which corresponds with the in vivo thymic regression observed in murine TLX1 tumor models, and creates a strong genetic pressure for acquiring activating NOTCH1 mutations as a prerequisite for full leukemic transformation. In conclusion, our results uncover a functional antagonism between cooperative oncogenes during the earliest phases of tumor development and provide novel insights in the multistep pathogenesis of TLX1 driven human leukemia. Gene expression was measured after TLX1 overexpression in human CD34+ T-cell progenitors cultured on an OP9-DLL1 feeder layer. Cells were collected after 72h of co-culture. This was performed for 2 independent thymus CD34+ donors.
2015-08-05 | E-GEOD-62143 | biostudies-arrayexpress
Project description:Transgenic expression of TLX1 induces T-cell leukemias in mice. We used microarrays to identify the gene expression signatures associated with TLX1 tumors compared with different genetic models T acute lymphoblastic lymphoma. RNA extraction from T-cell tumors from mice with different T-cell lymphoma-predisposing genetic backgrouds.
2010-10-19 | E-GEOD-19499 | biostudies-arrayexpress