Mus musculus
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ABSTRACT:
PROVIDER: PRJNA98433 | ENA |
REPOSITORIES: ENA
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Project description:A single normal hematopoietic stem cell (HSC) is sufficient to regenerate the entire blood system after bone marrow transplantation. This process requires not only rapid mobilization of the stem cell into the cell cycle, but also the proliferation of committed progenitor cells to provide functional mature cells until HSC progeny have accumulated to sufficient numbers1. Gene disruption strategies have dissected the regulatory pathways and identified critical factors that mediate the decision of a stem cell to self-renew and quiesce or to enter the rapidly expanding progenitor cell pool to populate the various hematopoietic cell lineages. However, only a very limited number of the transcriptional regulators and chromatin remodeling factors that are recruited by DNA binding factors have been pinpointed as contributors to stem cell functions. Here, we show that the transcriptional co-repressor Myeloid Translocation Gene on chromosome 16 (Mtg16), which is targeted by the t(16;21) in acute myeloid leukemia, is required for long-term hematopoietic stem cell functions and suppression of stem cell mobilization. Although there are no dramatic defects in the allocation of cells to any of the major hematopoietic cell lineages, inactivation of Mtg16 impairs the rapid expansion of stem/progenitor cells, which is required after bone marrow transplantation. This impairment appears to be a failure to proliferate rather than an induction of cell death, as expression of c-Myc complements the Mtg16-/- defect. Keywords: Knock-out analysis, genetic modification
2008-02-21 | GSE7106 | GEO
Project description:Aberrant epithelial differentiation and regeneration contribute to colon pathologies, including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Myeloid translocation gene 16 (MTG16, also known as CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 deficiency in mice exacerbates colitis and increases tumor burden in CAC, though the underlying mechanisms remain unclear. Here, we identified MTG16 as a central mediator of epithelial differentiation, promoting goblet and restraining enteroendocrine cell development in homeostasis and enabling regeneration following dextran sulfate sodium–induced (DSS-induced) colitis. Transcriptomic analyses implicated increased Ephrussi box–binding transcription factor (E protein) activity in MTG16-deficient colon crypts. Using a mouse model homozygous for a point mutation that attenuates MTG16:E protein interactions (Mtg16P209T), we showed that MTG16 exerts control over colonic epithelial differentiation and regeneration by repressing E protein–mediated transcription. Mimicking murine colitis, MTG16 expression was increased in biopsies from patients with active IBD compared with unaffected controls. Finally, uncoupling MTG16:E protein interactions partially phenocopied the enhanced tumorigenicity of Mtg16-null colon in the azoxymethane (AOM) /DSS-induced model of CAC, indicating that MTG16 protects from tumorigenesis through additional mechanisms. Collectively, our results demonstrate that MTG16, via its repression of E protein targets, is a key regulator of cell fate decisions during colon homeostasis, colitis, and cancer.
2022-05-01 | GSE201768 | GEO
Project description:The overall aim of the present work was to identify MTG16 functions in leukemia cells. Alterations in quantity of the MTG16 co-repressor might affect gene regulation and cell metabolism in malignant cells. Differentiated cells secure energy for cellular homeostasis largely by mitochondrial oxidation. Whereas, mature cells, proliferating tumour cells including leukemia cells depend on glycolysis and mitochondrial respiration may be low even in oxygen–rich environments.The same signal transduction pathways that govern cell proliferation give instructions for nutrient uptake and co-regulate metabolic processes. In this manner, the metabolism of tumor cells, and other highly proliferating cells, is adapted to stimulate anabolic glycolysis–driven processes for incorporation of nutrients into nucleotides, amino acids and lipids to synthesize macromolecules required for growth and proliferation. We used a doxycycline–regulated Tet-On gene expression system to achieve controlled expression of MTG16. A noticeable finding was that the expression of genes for key glycolytic regulators involved in aerobic tumor cell glycolysis was diminished by MTG16.
2012-12-04 | GSE42682 | GEO
Project description:The overall aim of the present work was to identify MTG16 functions in leukemia cells. Alterations in quantity of the MTG16 co-repressor might affect gene regulation and cell metabolism in malignant cells. Differentiated cells secure energy for cellular homeostasis largely by mitochondrial oxidation. Whereas, mature cells, proliferating tumour cells including leukemia cells depend on glycolysis and mitochondrial respiration may be low even in oxygen–rich environments.The same signal transduction pathways that govern cell proliferation give instructions for nutrient uptake and co-regulate metabolic processes. In this manner, the metabolism of tumor cells, and other highly proliferating cells, is adapted to stimulate anabolic glycolysis–driven processes for incorporation of nutrients into nucleotides, amino acids and lipids to synthesize macromolecules required for growth and proliferation. We used a doxycycline–regulated Tet-On gene expression system to achieve controlled expression of MTG16. A noticeable finding was that the expression of genes for key glycolytic regulators involved in aerobic tumor cell glycolysis was diminished by MTG16. Total cellular RNA was extracted from Raji/MTG16 Tet-On 3G cells after 8 hours of incubation with 1 mg/ml doxycycline. Cells were collected in triplicates as biological replicates. Total RNA was isolated using the RNeasy mini kit. The quality of RNA was examined by Bioanalyzer.RevertAidTM was used for synthesis of first strand cDNA from 1mg RNA using random primers.Microarray analysis was performed using Affymetrix expression system at SCIBLU Genomics.
2012-12-04 | E-GEOD-42682 | biostudies-arrayexpress
Project description:Transforming growth factor-β (TGFβ) is a potent inhibitor of hematopoietic stem cell (HSC) proliferation. However, the precise mechanism for this effect is unknown. Here, we have identified the transcription factor Gata2, previously described as an important regulator of HSC function, as an early and direct target gene for TGFβ-induced Smad signaling in hematopoietic stem and progenitor cells (HSPCs). Interestingly, TGFβ-induced Gata2 upregulation is critical for subsequent transcriptional activation of the TGFβ signaling effector molecule p57 and resulting growth arrest of HSPCs. Importantly, both Gata2 and p57 are abundantly expressed in freshly isolated highly purified HSCs, demonstrating the relevance of this circuit in HSC regulation within the HSC niche. Our results connect key molecules involved in HSC self-renewal and reveal a functionally relevant network regulating proliferation of primitive hematopoietic cells. To identify early gene targets of TGFβ signaling in hematopoietic progenitor cells, we performed high-throughput gene expression profiling of a primitive murine hematopoietic cell line. One of the revealed target genes was the transcription factor Gata2, which became the base for the rest of the study. Three independent RNA harvests were separately analyzed. Untreated cells were used as controls to the 10ng/ml TGFb-treated cells.
2016-09-01 | E-GEOD-73567 | biostudies-arrayexpress
Project description:To uphold appropriate homeostasis of short-lived blood cells, immature blood cells need to proliferate vigorously. Here, using a conditional H2B-mCherry labeling mouse-model, we characterize hematopoietic stem cell (HSC) and progenitor proliferation dynamics in steady state, upon physiological aging and following several types of induced stress. Following transplantation, HSCs shifted towards higher degrees of proliferation that was sustained long-term. HSCs were, by contrast, poorly recruited into proliferation following cytokine-induced mobilization and after acute depletions of selected blood cell lineages. Using indexed single cell sorting coupled to multiplex gene expression analyses, proliferation history separated candidate HSCs into units with distinct molecular and functional attributes. Our data thereby highlight that HSC proliferation following transplantation is fundamentally different not only from native hematopoiesis but also from other stress contexts, and demonstrate the power of divisional history as a functional criterion to resolve HSC heterogeneity.
2016-03-18 | GSE77477 | GEO
Project description:The myeloid translocation gene family member MTG16 is a transcriptional corepressor that relies on the DNA-binding ability of other proteins to determine specificity. One such protein is the ZBTB family member Kaiso, and the MTG16:Kaiso interaction is necessary for repression of Kaiso target genes such as matrix metalloproteinase-7. Using the azoxymethane and dextran sodium sulfate (AOM/DSS) murine model of colitis-associated carcinoma, we previously determined that MTG16 loss accelerates tumorigenesis and inflammation. However, it was unknown whether this effect was modified by Kaiso-dependent transcriptional repression. To test for a genetic interaction between MTG16 and Kaiso in inflammatory carcinogenesis, we subjected single and double knockout (DKO) mice to the AOM/DSS protocol. Mtg16-/- mice demonstrated increased colitis and tumor burden; in contrast, disease severity in Kaiso-/- mice was equivalent to wild type controls. Surprisingly, Kaiso deficiency in the context of MTG16 loss reversed injury and pro-tumorigenic responses in the intestinal epithelium following AOM/DSS treatment, and tumor numbers were returned to near to wild type levels. Transcriptomic analysis of non-tumor colon tissue demonstrated that changes induced by MTG16 loss were widely mitigated by concurrent Kaiso loss, and DKO mice demonstrated downregulation of metabolism and cytokine-associated gene sets with concurrent activation of DNA damage checkpoint pathways as compared with Mtg16-/-. Further, Kaiso knockdown in intestinal enteroids reduced stem- and WNT-associated phenotypes, thus abrogating the induction of these pathways observed in Mtg16-/- samples. Together, these data suggest that Kaiso modifies MTG16-driven inflammation and tumorigenesis and suggests that Kaiso deregulation contributes to MTG16-dependent colitis and CAC phenotypes.
2019-04-02 | GSE124544 | GEO
Project description:The neurotransmitter receptor Gabbr1 regulates proliferation and function of hematopoietic stem and progenitor cells
| PRJNA661041 | ENA
Project description:microRNAs (miRNAs) are abundant, ~21 nucleotide (nt) non-coding regulatory RNAs. Each miRNA may regulate hundreds of mRNA targets, but the identities of these targets and the processes they regulate are poorly understood. Here we have explored the use of microarray profiling and functional screening to identify targets and biological processes triggered by transfection of miRNAs into human cells. We demonstrate that a family of miRNAs sharing sequence identity with miR-16 negatively regulates cellular growth and cell cycle progression. miR-16 down-regulated transcripts were enriched for genes whose silencing by siRNAs causes cell cycle accumulation at G0/G1. Simultaneous silencing of these genes was more effective at blocking cell cycle progression than disruption of the individual genes. Thus, miR-16 coordinately regulates targets that may act in concert to control cell cycle progression. Keywords: miRNA, microRNA, miR-16, target, cell cycle, G0/G1, microarray profiling, functional screen,
2007-02-01 | GSE6838 | GEO
Project description:murine hematopoietic stem progenitor cells proteome Raw data
2024-05-16 | PXD052330 |