Expression data of LPS-stimulated bone marrow macrophages induced by M-CSF from wild-type and Jmjd3-/- mice.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE23180 | GEO | 2010/08/22
SECONDARY ACCESSION(S): PRJNA133265
REPOSITORIES: GEO
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Project description:Purpose: The goals of this study are to compare NGS-derived GM-CSF-cultured bone marrow derived cells transcriptome profiling (RNA-seq) normalized counts and differential expression of genes between different stimulations (untreated, Beauvericin, LPS or Beauvericin with LPS). Methods: mRNA profiles of GM-CSF-cultured bone marrow derived FACS purified MHCII high CD11c+ cells from wild-type C57BL/6N mice that were left untreated or stimulated with Beauvericin, LPS or Beauvericin with LPS for 4h were generated by deep sequencing, in quadruplicate, using the Illumina NextSeq550 system. DNase digested total RNA samples used for transcriptome analyses were quantified (Qubit RNA HS Assay, Thermo Fisher Scientific) and quality measured by capillary electrophoresis using the Fragment Analyzer and the ‘Total RNA Standard Sensitivity Assay’ Results: The reads of all probes were adapter trimmed (Illumina TruSeq). Mapping was done against the Mus musculus (mm39; GRCm39) (June 24, 2020) genome sequence. After grouping of samples (four biological replicates each) according to their respective experimental condition, multi-group comparisons were made and statistically determined using DESeq2. The Resulting P values were corrected for multiple testing by FDR. A P value of <0.05 was considered significant. Conclusions: Our study represents the first detailed analysis of untreated and Beauvericin stimulated GM-CSF-cultured bone marrow derived cells transcriptomes.Our results show that NGS offers a comprehensive and more accurate quantitative and qualitative evaluation of mRNA content within GM-CSF-cultured bone marrow derived cells. We conclude that Beauvericin activates GM-CSF-cultured bone marrow derived cells inducing inflammatory cytokine,chemokine and Type I IFN production via a TLR4 dependent signaling pathway, but induces a gene expression profile different from LPS.
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Project description:Lipopolysaccharide (LPS) can either promote or prevent T helper-2 (Th2) cell-allergic responses. However, the underlying mechanism remains unknown. We show here that LPS activity switches from pro-pathogenic to protective depending on the production of GM-CSF by non-classical monocytes. In the absence of GM-CSF, LPS can favor pathogenic Th2 cell responses by supporting the trafficking of lung migratory dendritic cells (mDC2s) into the lung-draining lymph node. However, when non-classical monocytes produce GM-CSF, LPS and GM-CSF synergize to differentiate monocyte-derived DCs (moDCs) that instruct mDC2s for Th2 cell suppression. Importantly, only allergens with cysteine protease activity trigger GM-CSF production by non-classical monocytes. Hence, the therapeutic effect of LPS is restricted to allergens with this enzymatic activity. Treatment with GM-CSF, however, restores the protective effects of LPS. Thus, GM-CSF produced by non-classical monocytes acts as a rheostat that fine-tunes the pathogenic and therapeutic functions of LPS.
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Project description:Inflammatory responses triggered by either microbial or endogenous stimuli rely on a complex transcriptional program that involves the differential expression of hundreds of genes. Jmjd3, a JmjC family histone demethylase (HDM), is quickly induced by the transcription factor NF-kB in response to inflammatory stimuli. Jmjd3 erases a histone mark associated with transcriptional repression and silencing, trimethylated lysine 27 in histone H3 (H3K27me3). Thus, Jmjd3-mediated demethylation of H3K27me3 links inflammation to the control of a histone modification involved in lineage determination, differentiation and tissue homeostasis. However, the specific contribution of Jmjd3 induction to innate immunity and inflammation remains unknown. Here we combined genome-wide mapping and gene knockout studies to investigate this issue. Chromatin immunoprecipitation (ChIP) coupled to ultra high-throughput sequencing (ChIP-Seq) in LPS-stimulated primary mouse macrophages demonstrated that Jmid3 is recruited to a large number of genomic targets with a strong preference for active transcription start sites (TSS). Virtually all Jmjd3-bound TSSs were characterized by high levels of H3K4me3, a marker of gene activity, and high levels of RNA polymerase II (Pol_II). Inducible genes showing a strong increase in H3K4me3 and Pol_II recruitment after endotoxin treatment (including those encoding several cytokines, chemokines and antiviral proteins) were in most cases Jmjd3-associated. In Jmjd3-knockout macrophages, initial RNA_Pol II recruitment and activation of Jmjd3 target genes was unaffected, but RNA_Pol II was prematurely released, thus resulting in non-sustained responses. Importantly, most Jmjd3 target genes were not associated with detectable levels of H3K27me3, and transcriptional effects of Jmjd3 absence in the window of time analyzed here were uncoupled from measurable effects on this histone mark. Our data indicate that Jmjd3 is the effector of an NF-kB-controlled feed-forward transcriptional loop pervasively sustaining inflammatory transcriptional responses in a manner that is independent of H3K27me3 demethylation, and suggest the possible use of anti-Jmjd3 drugs to dampen pathologic inflammation. Keywords: Epigenetics Genome wide maps of histone demethylase jmjd3, the histone marks H3K4me3 and H3K27me3, and RNA-Polymerase II induction in mouse bone marrow-derived macrophages of two types: (a) untreated and (b) stimulated with lipopolysaccharide and interferon gamma to produce an inflammatory response.
2009-11-23 | E-GEOD-17631 | biostudies-arrayexpress
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Project description:Jmjd3 is trimethyl H3K27 specific demethylase required for M2 macrophage polarization. Genomic fragments obtained from wild-type and Jmjd3-/- mouse macrophages were immunoprecipitated with anti H3K27me3 Ab, and deep sequencing was performed. wild-type and Jmjd3-/- macrophages
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Project description:Polarization of macrophages to M1 or M2 cells is important for mounting responses against bacterial and helminth infection respectively. Jumonji domain containing 3 (JMJD3), a histone 3 K27 demethylase, has been implicated in the activation of macrophages. Here we show that JMJD3 is essential for M2 macrophage polarization to helminth infection and chitin, though JMJD3 is dispensable for M1 responses. Furthermore, Jmjd3 is critical for proper bone marrow macrophage differentiation in a demethylase activity-dependent manner. Jmjd3 deficiency affected trimethylation of H3K27 in only a limited numbers of genes. Among them, we identified Irf4 as the target transcription factor critical for controlling M2 macrophage polarization. Collectively, these results show that JMJD3-mediated H3K27 demethylation is critical for regulating M2 macrophage development leading to anti-helminth host responses. This SuperSeries is composed of the SubSeries listed below.
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Project description:GM-CSF derived bone marrow cultures contain several subsets of CD11c+MHCII+ mononuclear phagocytes Using Affymetrix microarrays we compared gene expression of the different mononuclear phagocytes within the bone marrow culture. The different populations are left unstimulated or are stimulated with LPS The Affymetrix GeneChip Mouse Gene 1.0 arrays were used to define gene expression profiles in the different population.
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Project description:Jmjd3 is trimethyl H3K27 specific demethylase required for M2 macrophage polarization. Genomic fragments obtained from wild-type and Jmjd3-/- mouse macrophages were immunoprecipitated with anti H3K27me3 Ab, and deep sequencing was performed.
2010-08-22 | GSE23297 | GEO
Project description:Inflammatory responses triggered by either microbial or endogenous stimuli rely on a complex transcriptional program that involves the differential expression of hundreds of genes. Jmjd3, a JmjC family histone demethylase (HDM), is quickly induced by the transcription factor NF-kB in response to inflammatory stimuli. Jmjd3 erases a histone mark associated with transcriptional repression and silencing, trimethylated lysine 27 in histone H3 (H3K27me3). Thus, Jmjd3-mediated demethylation of H3K27me3 links inflammation to the control of a histone modification involved in lineage determination, differentiation and tissue homeostasis. However, the specific contribution of Jmjd3 induction to innate immunity and inflammation remains unknown. Here we combined genome-wide mapping and gene knockout studies to investigate this issue. Chromatin immunoprecipitation (ChIP) coupled to ultra high-throughput sequencing (ChIP-Seq) in LPS-stimulated primary mouse macrophages demonstrated that Jmid3 is recruited to a large number of genomic targets with a strong preference for active transcription start sites (TSS). Virtually all Jmjd3-bound TSSs were characterized by high levels of H3K4me3, a marker of gene activity, and high levels of RNA polymerase II (Pol_II). Inducible genes showing a strong increase in H3K4me3 and Pol_II recruitment after endotoxin treatment (including those encoding several cytokines, chemokines and antiviral proteins) were in most cases Jmjd3-associated. In Jmjd3-knockout macrophages, initial RNA_Pol II recruitment and activation of Jmjd3 target genes was unaffected, but RNA_Pol II was prematurely released, thus resulting in non-sustained responses. Importantly, most Jmjd3 target genes were not associated with detectable levels of H3K27me3, and transcriptional effects of Jmjd3 absence in the window of time analyzed here were uncoupled from measurable effects on this histone mark. Our data indicate that Jmjd3 is the effector of an NF-kB-controlled feed-forward transcriptional loop pervasively sustaining inflammatory transcriptional responses in a manner that is independent of H3K27me3 demethylation, and suggest the possible use of anti-Jmjd3 drugs to dampen pathologic inflammation. Keywords: Epigenetics
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