Tet2 loss dysregulates the behavior of bone marrow derived mesenchymal stromal cells [RNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE100071 | GEO | 2018/02/13
REPOSITORIES: GEO
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Project description:TET2 plays an important role in regulating the behavior of bone marrow derived MSCs in addition to its intrinsic role in HSPCs to participate in aberrant hematopoiesis. Moreover, MSCs are the most important niche cell components in Tet2-/- mice that contribute to the progression of Tet2 deletion-driven myeloid malignancies. This SuperSeries is composed of the SubSeries listed below.
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Project description:TET2 is a methylcytosine dioxygenase that regulates cytosine hydroxymethylation. Although there are extensive data implicating a pivotal role of TET2 in hematopoietic stem/progenitor cells (HSPCs), the importance of TET2 in bone marrow mesenchymal stromal cells (BMSCs) remains unknown. In this study, we show that loss of TET2 in BMSCs increases cell proliferation and self-renewal and enhances osteoblast differentiation potential of BMSCs, which may in turn alter their behavior in supporting HSPC proliferation and differentiation. In addition, Tet2 loss alters BMSCs in promoting Tet2-deficiency-mediated myeloid malignancy progression. Tet2 loss in BMSCs also dysregulates hydroxylation of 5-methylcytosine (5mC) and the expression of genes that are key for BMSC proliferation and osteoblast differentiation, leading to alteration of biological characteristics in vivo. These results highlight the critical role of TET2 in the maintenance of BMSC functions and osteoblast differentiation and provide evidence that dysregulation of epigenetic modifiers in BMSCs contributes to the progression of myeloid malignancies.
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Project description:Tet2 loss dysregulates the behavior of bone marrow derived mesenchymal stromal cells
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Project description:Recent studies have shown that both TET2 mutation and JAK2V617F mutation are frequent in myeloproliferative neoplasms patients. The pathophysiological roles of each mutation have been elucidated in murine models, but the cooperative effect of the two mutations has not been elucidated yet. In this study, we examined the function of the cooperative effect of loss-of-TET2 function and JAK2V617F mutation in murine hematopoiesis. In this study, we utilized wild type (WT) mice, TET2 knock down (TET2KD) mice, JAK2V617F transgenic mice, double mutant mice. We transplanted 4 types of E14.5 fetal liver cells (WT, TET2KD, JAK2V617F, double mutant) into lethally irradiated mice. At 10-16 weeks post-transplantation, LSK cells from the BM of the recipients were collected, and gene expression analysis was performed. (WT,5 mice at 16 weeks; TET2KD, 5 mice at 10 weeks; JAK2V617F, 5 mice at 16 weeks; double mutant, 5 mice at 13 weeks)
2014-10-16 | E-GEOD-62302 | biostudies-arrayexpress
Project description:In this study, we investigated the role of Tet2 in regulation of hematopoietic genes by performing transcriptomic analysis of Tet2 WT, Mut, and KO LSK and Lin– cells at 3, 6, 9, and 12 months by RNA-seq, and mapping the DNA methylation landscape of 3-month-old Tet2 WT, Mut, and KO LSK and Lin– cells. (1) We find that loss of Tet2 (Tet2 KO) vs. a loss of Tet2 catalytic function (Tet2 Mut) at different time points and cell types causes distinct gene expression changes when compared to WT samples as assessed by RNA-seq. (2) Additionally, we find that many genes implicated in lymphoma and leukemia are deregulated in Tet2 Mut and KO LSK and Lin– cells, consistent with the phenotypes observed in mice transplanted with Tet2 Mut and KO bone marrow. (3) We also mapped genome-wide DNA methylation levels of WT, Tet2 Mut, and KO LSK and Lin– cells at 3 months by WGBS and establish a role for Tet2 in demethylating genes implicated in lymphoma and leukemia initiation and progression.
2023-06-01 | GSE227977 | GEO
Project description:Recent studies have shown that both TET2 mutation and JAK2V617F mutation are frequent in myeloproliferative neoplasms patients. The pathophysiological roles of each mutation have been elucidated in murine models, but the cooperative effect of the two mutations has not been elucidated yet. In this study, we examined the function of the cooperative effect of loss-of-TET2 function and JAK2V617F mutation in murine hematopoiesis.
2014-10-16 | GSE62302 | GEO
Project description:Interfaces between soft tissue and bone are characterized by transitional gradients in composition and structure that mediate substantial changes in mechanical properties. For interfacial tissue engineering, scaffolds with mineral gradients have shown promise in controlling osteogenic behavior of seeded bone marrow stromal cells (bMSCs). Previously, we have demonstrated a 'top-down' method for creating monolithic bone-derived scaffolds with patterned mineral distributions similar to native tissue. In the present work, we evaluated the ability of these scaffolds to pattern osteogenic behavior in bMSCs in basic, osteogenic, and chondrogenic biochemical environments. Immunohistochemical (IHC) and histological stains were used to characterize cellular behavior as a function of local mineral content. Alkaline phosphatase, an early marker of osteogenesis, and osteocalcin, a late marker of osteogenesis, were positively correlated with mineral content in basic, osteogenic, and chondrogenic media. The difference in bMSC behavior between the mineralized and demineralized regions was most pronounced in an basic biochemical environment. In the mineralized regions of the scaffold, osteogenic markers were clearly present as early as 4 days in culture. In osteogenic media, osteogenic behavior was observed across the entire scaffold, whereas in chondrogenic media, there was an overall reduction in osteogenic biomarkers. Overall, these results indicate local mineral content of the scaffold plays a key role in spatially patterning bMSC behavior. Our results can be utilized for the development of interfacial tissue engineered scaffolds and understanding the role of local environment in determining bMSC behavior. STATEMENT OF SIGNIFICANCE: Soft tissue-to-bone interfaces, such as tendon-bone, ligament-bone, and cartilage-bone, are ubiquitous in mammalian musculoskeletal systems. These interfacial tissues have distinct, hierarchically-structured gradients of cellular, biochemical, and materials components. Given the complexity of the biological structures, interfacial tissues present unique challenges for tissue engineering. Here, we demonstrate that material-derived cues can spatially pattern osteogenic behavior in bone marrow stromal cells (bMSCs). Specifically, we observed that when the bMSCs are cultured on bone-derived scaffolds with mineral gradients, cells in contact with higher mineral content display osteogenic behavior at earlier times than those on the unmineralized substrate. The ability to pattern the cellular complexity found in native interfaces while maintaining biologically relevant structures is a key step towards creating engineered tissue interfaces.
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Project description:Somatic or de novo mutations of Additional sex combs-like 1 (ASXL1) frequently occur in patients with myeloid malignancies or Bohring-Opitz syndrome, respectively. We have reported that global loss of Asxl1 leads to the development of myeloid malignancies and impairs bone marrow stromal cell (BMSC) fates in mice. However, the impact of Asxl1 deletion in the BM niche on hematopoiesis remains unclear. Here, we showed that BMSCs derived from chronic myelomonocytic leukemia patients had reduced expression of ASXL1, which impaired the maintaining cord blood CD34+ cell colony-forming capacity with a myeloid differentiation bias. Furthermore, Asxl1 deletion in the mouse BMSCs altered hematopoietic stem and progenitor cell (HSC/HPC) pool and a preferential myeloid lineage increment. Immunoprecipitation and ChIP-seq analyses demonstrated a novel interaction of ASXL1 with the core subunits of RNA polymerase II (RNAPII) complex. Convergent analyses of RNA-seq and ChIP-seq data revealed that loss of Asxl1 deregulated RNAPII transcriptional function and altered the expression of genes critical for HSC/HPC maintenance, such as Vcam1. Altogether, our study provides a mechanistic insight into the function of ASXL1 in the niche to maintain normal hematopoiesis; and ASXL1 alteration in, at least, a subset of the niche cells induces myeloid differentiation bias, thus, contributes the progression of myeloid malignancies.
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Project description:BackgroundOsteogenesis Imperfecta (OI) (OMIM %259450) is a heterogeneous group of inherited disorders characterized by increased bone fragility, with clinical severity ranging from mild to lethal. The majority of OI cases are caused by mutations in COL1A1 or COL1A2. Bruck Syndrome (BS) is a further recessively-inherited OI-like phenotype in which bone fragility is associated with the unusual finding of pterygia and contractures of the large joints. Notably, several studies have failed to show any abnormalities in the biosynthesis of collagen 1 in BS patientes. Evidence was obtained for a specific defect of the procollagen telopeptide lysine hydroxylation in BS, whereas mutations in the gene PLOD2 have been identified. Recently, several studies described FKBP10 mutations in OI-like and BS patients, suggesting that FKBP10 is a bonafide BS locus.MethodsWe analyzed the coding region and intron/exon boundaries of COL1A1, COL1A2, PLOD2 and FKBP10 genes by sequence analysis using an ABI PRISM 3130 automated sequencer and Big Dye Terminator Sequencing protocol. Mononuclear cells obtained from the bone marrow of BS, OI patients and healthy donors were cultured and osteogenic differentiation was induced. The gene expression of osteoblast specific markers were also evaluated during the osteoblastic differentiation of mesenchymal stem cell (MSC) by qRT-PCR using an ABI7500 Sequence Detection System.ResultsNo mutations in COL1A1, COL1A2 or PLOD2 were found in BS patient. We found a homozygous 1-base-pair duplication (c.831dupC) that is predicted to produce a translational frameshift mutation and a premature protein truncation 17 aminoacids downstream (p.Gly278ArgfsX95). The gene expression of osteoblast specific markers BGLAP, COL1A1, MSX2, SPARC and VDR was evaluated by Real Time RT-PCR during differentiation into osteoblasts and results showed similar patterns of osteoblast markers expression in BS and healthy controls. On the other hand, when compared with OI patients, the expression pattern of these genes was found to be different.ConclusionsOur work suggests that the gene expression profiles observed during mesenchymal stromal cell differentiation into osteoblast are distinct in BS patients as compared to OI patients. The present study shows for the first time that genes involved in osteogenesis are differentially expressed in BS and OI patients.
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