The present study was designed using MT knockout mice in concert with genomic approaches to explore the possible molecular and cellular mechanisms involved in the protective effects of MT against DOX cardiotoxicity. MT-/ null (MT-/-) mice and corresponding wild-type mice (MT+/+) were administrated with a single dose of DOX (15 mg/kg, i.p.) or an equal volume of saline. Animals were sacrificed on the 4th day after DOX administration and samples were collected for further analyses. Global gene expression profiles of cardiac mRNA from two genotype mice revealed that 381 characteristically MT-responsive genes were identified between MT+/+ mice and MT-/- mice in response to DOX, including fos, ucp3, car3, atf3, map3k6, etc.. Functional analysis implied MAPK signaling pathway, p53 signaling pathway, Jak-STAT signaling pathway, PPAR signaling pathway, Wnt signaling pathway, etc. might be involved to mediate the protection of DOX cardiomyopathy by MT. Results from the present study not only validated the previously reported possible mechanisms of MT protection against DOX toxicity, but also provided new clues into the molecular mechanisms involved in this process.
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Specimen part
View SamplesIdentification of cancer stem/initiating cells (CSCs/CICs) by a specific marker is useful for diagnosis and therapy of cancer. We have determined that PSF1 which plays a role in DNA replication in lower species is strongly expressed in wide range of normal stem cell population. Here, utilizing the transcriptional activity of PSF1 promoter in tumor cell xenograft model, we show that PSF1high cancer cells display malignant features including high proliferating activity, serial transplantation potential, and metastatic ability those are used for criteria of CSCs/CICs. PSF1high cancer cells localize in perivascular region and genetically display ES cell like signature. Silencing of PSF1 by RNAi inhibited growth of cancer cells mediated by disruption of DNA synthesis and chromosomal segregation. These suggested that PSF1 is a possible maker and a molecular target of CSCs/CICs.
No associated publication
Cell line
View SamplesWe generated three kinds of genetically identical mouse reprogrammed cells: induced pluripotent stem cells (iPSCs), nuclear transfer embryonic stem cells (ntESCs) and iPSC-nt-ESCs that are established after successively reprogramming of iPSCs by nuclear transfer (NT). NtESCs show better developmental potential than iPSCs, whereas iPSC-nt-ESCs display worse developmental potential than iPSCs.
Different developmental potential of pluripotent stem cells generated by different reprogramming strategies.
Sex, Specimen part, Cell line
View SamplesPolycomb group (PcG) proteins control organism development by regulating the expression of developmental genes. Transcriptional regulation by PcG proteins is achieved at least partly through the PRC2-mediated methylation on lysine 27 of histone H3 (H3K27) and PRC1-mediated ubiquitylation on lysine 119 of histone H2A (uH2A). As an integral component of PRC1, Bmi1 has been demonstrated to be critical for H2A ubiquitylation. Although recent studies have revealed the genome wide binding patterns of some of the PRC1 and PRC2 components, as well as the H3K27me3 mark, there have been no reports describing genome wide localization of uH2A. Using the recently developed ChIP-Seq technology, here we report genome wide localization of the Bmi1-dependent uH2A mark in MEF cells. Gene promoter averaging analysis indicates a peak of uH2A just inside the transcription start site (TSS) of well annotated genes. This peak is enriched at promoters containing the H3K27me3 mark and represents the least expressed genes in WT MEF cells. In addition, peak finding reveals regions of local uH2A enrichment throughout the mouse genome, including almost 700 gene promoters. Genes with promoter peaks of uH2A exhibit lower level expression when compared to genes that do not contain promoter peaks of uH2A. Moreover, we demonstrate that genes with uH2A peaks have increased expression upon Bmi1 knockout. Importantly, local enrichment of uH2A is not limited to regions containing the H3K27me3 mark. We provide evidence to suggest that DNA methylation is tightly linked to H2A ubiquitylation in high density CpG promoters. Thus, our work not only reveals Bmi1-dependent H2A ubiquitylation but also suggests that uH2A targeting in differentiated cells may employ a different mechanism from that in ES cells.
Genome-wide uH2A localization analysis highlights Bmi1-dependent deposition of the mark at repressed genes.
Sex
View SamplesGene expression changes in mouse skeletal muscle were assessed in wild-type and Jhdm2a null skeletal muscle in an effort to define the role of Jhdm2a in energy expenditure and metabolism.
Role of Jhdm2a in regulating metabolic gene expression and obesity resistance.
Sex, Age, Specimen part
View SamplesThe activation of different oncogenic signals may primarily contribute to the heterogeneity of cancer cells. However, the exact mechanisms underlying different oncogenic transformation are still unclear. We used the c-Myc, H-Ras and Akt transformed liver cell model to define mRNA expression profiles in the non-transformed and the three types of oncogene-transformed cells
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View SamplesThe serine threonine kinase Stk40 has been shown to involve in mouse embryonic stem cell differentiation, pulmonary maturation and adipocyte differentiation. Here we report that targeted deletion of Stk40 leads to fetal liver hypoplasia and anemia in the mouse embryos. The reduction of erythrocytes in the fetal liver is accompanied by increased apoptosis and compromised erythroid maturation. Stk40-/- fetal liver cells have significantly reduced colony forming units (CFUs) capable of erythroid differentiation, including burst forming unit-erythroid (BFU-E), colony forming unit-erythroid (CFU-E), and CFU-granulocyte, erythrocyte, megakaryocyte and macrophage (CFU-GEMM), but not CFU-granulocyte/macrophages (CFU-GM). Purified Stk40-/- megakaryocyte-erythrocyte progenitors (MEPs) produced substantially fewer CFU-E colonies compared to control cells. Moreover, Stk40-/- fetal liver erythroblasts failed to form normal erythroblastic islands in association with wild type or Stk40-/- macrophages, indicating an intrinsic defect of Stk40-/- erythroblasts. Furthermore, the hematopoietic stem and progenitor cell pool is reduced in Stk40-/- fetal livers but still retains the multi-lineage reconstitution capacity. Finally, analysis of microarray data of E14.5 fetal liver cells suggests a potential role of aberrantly activated TNF- signaling in Stk40 depletion induced dyserythropoiesis with a concomitant increase in cleaved Caspase-3 and decrease in Gata1 proteins. Altogether, the identification of Stk40 as a regulator for fetal erythroid differentiation, maturation and survival provides new clues to the molecular regulation of erythropoiesis and related diseases.
No associated publication
Specimen part
View SamplesMesenchymal stem cells (MSCs) have been shown to exert therapeutic effects on various autoimmune diseases. However, such therapeutic effect is not always achieved. Among many reasons, MSC culture methodologies may account for the these differences. It is known that oxygen concentration could profoundly affect the properties of MSCs. Therefore, we compared human umbilical cord derived MSCs cultured under hypoxic and normoxic conditions.
No associated publication
Specimen part
View SamplesOne of the central issues in evolutionary developmental biology is how we can formulate the relationships between evolutionary and developmental processes. Two major models have been proposed: the 'funnel-like' model, in which the earliest embryo shows the most conserved morphological pattern, followed by diversifying later stages, and the 'hourglass' model, in which constraints are imposed to conserve organogenesis stages, which is called the phylotypic period. Here we perform a quantitative comparative transcriptome analysis of several model vertebrate embryos and show that the pharyngula stage is most conserved, whereas earlier and later stages are rather divergent. These results allow us to predict approximate developmental timetables between different species, and indicate that pharyngula embryos have the most conserved gene expression profiles, which may be the source of the basic body plan of vertebrates.
Comparative transcriptome analysis reveals vertebrate phylotypic period during organogenesis.
Sex, Specimen part, Disease, Disease stage
View SamplesTranscription profiling of mouse development
Comparative transcriptome analysis reveals vertebrate phylotypic period during organogenesis.
Sex, Specimen part, Disease, Disease stage
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