HDAC1 and 2 repress lineage inappropriate expression of Flt3 and Ptprf in B cells via Pax5 and Grg4
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Tim Roloff
PROVIDER: E-GEOD-36564 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Total RNA was isolated from pre BI (early lymphcytes) cells sorted by FACS with the following markers: B220+, CD25-, C-kit+,IgM-, CD19+. The animals used carried floxed Hdac1 & 2 either in combination with mb1-cre (refered to as DKO) or not (WT).
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Project description:This is one of expressional parts of the study. These data were correlated to epigenetic changes and CG density of genes in analyzed cells. The whole study has a following summary: To elucidate possible roles of DNA methylation and chromatin marks in transcription, we performed epigenetic profiling of chromosome 19 in human bronchial epithelial cells (HBEC) and in the colorectal cancer cell line HCT116 as well as its counterpart with double knockout of DNMT1 and DNMT3B (HCT116-DKO). We found that H3K9me3 forms intragenic chromatin blocks along genes with low CpG density in the gene body. Analysis of H3K36me3 profiles indicated that this mark associates either with active genes with low CpG density and H3K9me3 in the gene body or with active genes with high CpG density and DNA hypermethylation in the gene body. In HCT116 cells with double knockout of DNMT1 and DNMT3B, transcription of genes with low CpG density in the gene body was highly elevated and associated with promoter DNA demethylation and rearrangement of H3K9me3 and H3K36me3 occupation. Our finding suggests that similar to DNA methylation, H3K9me3 may play a role in intragenic gene regulation. Further, we observed that a combination of low CpG density in gene bodies together with H3K9me3 and H3K36me3 marking is a specific epigenetic feature of zinc finger (ZNF) genes, which comprise 90% of all genes carrying both histone marks on chromosome 19. For high CpG density genes, transcription and H3K36me3 occupancy were not changed in condition of partial or intensive loss of DNA methylation in gene bodies in the HCT116-DKO cell line. siRNA experiments with SETD2 knockdown in both HBEC and HCT116-DKO cell lines failed to reduce DNA methylation in gene bodies under conditions of H3K36me3 depletion. Our study suggests that the H3K36me3 and DNA methylation marks in gene bodies are established independently from each other and points to similar functional roles of intragenic DNA methylation and intragenic H3K9me3 for CpG-rich and CpG-poor genes, respectively. To elucidate how a loss of DNA methylation affects a gene expression and epigenome we studied colon cancer cell line HCT116 and its derivative, HCT116 DNMT1-/- DNMT3b -/- (HCT116-DKO). According to previous studies HCT116-DKO is characterized by 95% of loss of DNA methylation. In HCT116 and HCT116-DKO cells, we profiled diverse epigenetic marks and gene expression. Further a crosstalk between epigenetic changes and transcriptional changes was analyzed. This is the expressional part of study.
2011-03-31 | E-GEOD-26018 | biostudies-arrayexpress
Project description:Mice with homozygous null mutations in the HDL receptor (SR-BI) and apoE genes (SR-BI KO/apoE double KO (dKO) mice) spontaneously develop occlusive, atherosclerotic coronary artery disease (CAD) and die prematurely (50% mortality at 42 days of age) on standard chow diet feeding. Microarray analysis was performed to investigate the changes in gene expression profiles during the development of spontaneous severe CAD, which includes myocardial infarction and heart failure. These data will provide new insights in understanding the pathophysiology of CAD. The whole Hearts from dKO or SR-BI+/- apoE-/- (HET) mice (n=9-12) were harvested at 21, 31 and 43 days of age, and analyzed using Affymetrix microarrays. dKO mice do not show detectable signs of CAD at 21 days of age, small myocardial infarction (MI) and heart failure at 31 days of age, and extensive MI and severe heart failure at 43 days of age (50% mortality at 42 days of age). Each mouse was assigned to one array. SR-BI+/- apoE-/- mice (HET) which do not develop detectable signs of CAD on chow diet were used as controls.The data also include those from probucol treated dKO and HET mice (n=2-8).
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Project description:In the present study, we investigated the importance of histone deacetylase 6 (HDAC6) for glucocorticoid receptor (GR) mediated effects on glucose metabolism, and its potential as a therapeutic target for the prevention of glucocorticoid (GC)-induced diabetes. Dexamethasone (dex)-induced hepatic glucose output and GR translocation were analysed in wildtype (wt) and HDAC6-deficient (HDAC6ko) mice. The effect of the specific HDAC6-inhibitor tubacin was analysed in-vitro. Wt and HDAC6ko mice were subjected to 3 weeks dex treatment before analysis of glucose and insulin tolerance. HDAC6ko mice showed impaired dex-induced hepatic GR translocation. Accordingly, dex induced expression of a large number of hepatic genes was significantly attenuated in mice lacking HDAC6 and by tubacin in-vitro. Glucose output of primary hepatocytes from HDAC6ko mice was diminished. A significant improvement of dex-induced whole-body glucose intolerance as well as insulin resistance in HDAC6ko mice compared to wt littermates was observed. The present study demonstrates that HDAC6 is an essential regulator of hepatic GC stimulated gluconeogenesis and impairment of whole body glucose metabolism through modification of GR nuclear translocation. Selective pharmacological inhibition of HDAC6 may provide a future therapeutic option against the pro-diabetogenic actions of GCs. In this dataset, we include the expression data obtained from isolated RNA of dissected mouse livers using wildtype and HDAC6 deficient animals which were treated over a timespan of 3 weeks with 1mg/kg dexamethasone and vehicle respectively. These data are used to show the hdac6-deficiency mediated attenuation of several dexamethasone induced genes. 12 samples in total were analyzed. 3 samples of different animals of each group (wt vehicle, wt dexamethasone, hdac6ko vehicle and hdac6ko dexamethasone)
2011-12-07 | E-GEOD-34229 | biostudies-arrayexpress
Project description:Endocrine therapy is the main therapeutic option for patients with estrogen receptor alpha positive (ER+) breast cancer. Nevertheless, most of them become estrogen-independent and relapse after the treatment. Ret is a tyrosine kinase receptor that shows elevated expression levels in ER+ human breast tumors. In this study, we demonstrate that activation of the Ret receptor promotes proliferation as well as cell migration irrespective of endocrine therapy. Microarray data show that Ret activation involves changes in the expression of inflammatory- and motility-related genes. In vivo treatment with a Ret pathway inhibitor in a ER+/Ret+ mouse mammary cancer model, reduces tumor growth and lung metastasis even after endocrine therapy. Additionally, we show a connection between Ret and inflammatory pathways. The pro-inflamatory cytokine IL6 lies at the core of this regulation, which involves a positive feedback loop with IL6 and the Ret pathway reciprocally stimulating each other to further leading metastasis risk. Our findings provide insight into endocrine resistance mechanism and point at the Ret pathway as a potential target for future therapies. In order to model letrozole-sensitive breast cancer we use aromatase expressing MCF7 cells (MCF7/Aro). Six-day treatment (6 days) of cultures with letrozole (L) or fulvestrant (F) reversed the proliferative effects of the exposure to the estrogen (E2) precursor androstenedione (D4A). The addition of only EtOH (E) to the cells was used as control condition of deprivation. Treatment with the Ret ligand GDNF (G) partially rescues the inhibition of estrogen-dependent proliferation in these cells. To go deeper insight into the pathways involved, we decided to perform a microarray following different treatments (1-8: E, E+G, D, D+G, L, L+G, F, F+G) used in proliferation assays. Three biological replicates (rep 1-3) were used to the array.
2013-09-25 | E-GEOD-41405 | biostudies-arrayexpress
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2011-09-22 | E-GEOD-30586 | biostudies-arrayexpress
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2012-05-31 | E-GEOD-22772 | biostudies-arrayexpress
Project description:In mammals, totipotent pre-implantation embryos are formed by fusion of highly differentiated oocytes and spermatozoa. Acquisition of totipotency concurs with remodeling of chromatin states of parental genomes (âepigenetic reprogrammingâ), changes in maternally contributed transcriptome and proteome, and zygotic genome activation. Genomes of mature germ cells are more proficient in supporting embryonic development than those of somatic cells. It is currently unknown whether transgenerational inheritance of chromatin states present in mature gametes underlies the efficacy of early embryonic development after natural conception. Here, we show that Ring1 and Rnf2, two core components of the Polycomb Repressive Complex 1 (PRC1), serve redundant gene regulatory functions during oogenesis that are required to support embryonic development beyond the two-cell stage. Numerous developmental regulatory genes that are established Polycomb targets in various somatic cell types are de-repressed in Ring1/Rnf2 double mutant (dm) fully grown germinal vesicle (GV) oocytes. Translation of tested aberrant maternal transcripts is, however, delayed until after fertilization. Exchange of maternal pro-nuclei between control and Ring1/Rnf2 maternally dm early zygotes demonstrates an essential role for Ring1 and Rnf2 during oogenesis in defining cytoplasmic and nuclear maternal contributions that are both essential for proper initiation of embryonic development. A large number of genes up-regulated in Ring1/Rnf2 dm GV oocytes harbor PRC2-mediated histone H3 lysine 27 trimethylation (H3K27me3) in spermatozoa and in embryonic stem cells (ESCs), and are repressed during normal oogenesis and early embryogenesis. These data strongly support the model that Polycomb acts in the female and male germline to silence differentiation inducing genes and to program chromatin states, thereby sustaining developmental potential across generations. Expression profiling of late 2-cell embryos was performed with the following genotypes: maternal Ring1-Rnf+ (control), maternal Ring1-Rnf2- (maternal Ring1/Rnf2 double mutant). These embryos were obtained by crossing Ring1-/-Rnf2F/F control females or Ring1-/-Rnf2F/F Zp3-cre expreimental females, respectively, to Ring1+/+Rnf2F/F control males. To distinguish between maternal transcripts present in the 2-cell embryo and newly (embryonicaly) transcribed transcripts, embryos from both genotypes were either not treated (expression profiling therefore shows all maternal and embryonic transcripts) or alpha-amanitin treated (alpha-amanitin inhibits de novo transcription, therefore expression profiling of treated embryos will only show maternal transcripts). 11 samples were analyzed: 3 biological replicates (except alpha-amanitin treated maternal Ring1/Rnf2 double mutant, where only 2 replicates were analyzed) of each genotype and treatment group were analyzed. Each sample contains 40 late 2-cell embryos.
2012-05-06 | E-GEOD-28710 | biostudies-arrayexpress