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A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells [ChIP-Seq]

ABSTRACT: Dendritic cells (DCs) direct CD4+ T cell differentiation into distinct T helper (Th) subsets that are vital for protection against diverse types of infection. However, the mechanisms employed by DCs to initiate Th2 responses, which are important for immunity to helminth infection as well as being a major contributor to allergic disease, remain poorly understood. We demonstrate a key role for methyl-CpG-binding domain-2 (Mbd2), a protein that links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function. In the absence of Mbd2, DCs displayed reduced phenotypic activation and a dramatically impaired ability to promote Th2 immunity against either helminths or allergens, while their induction of Th1/17 responses remained intact. These data reveal a novel epigenetic mechanism that is integral to DC promotion of CD4+ T cell responses, particularly in Th2 settings, and identify methyl-CpG-binding proteins and the genes that they control as potential therapeutic targets for type-2 inflammation. H3K9,K14ac (H3ac) occupancy was analysed by ChIP-Seq for control (wt) or Mbd2 -/- (DEL) dendritic cells (DC). Input DNA for each cell line was also sequenced alongside.

ORGANISM(S): Mus musculus

SUBMITTER: Alasdair Ivens

PROVIDER: E-GEOD-66198 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells [gene expression]

Project description:Dendritic cells (DCs) direct CD4+ T cell differentiation into distinct T helper (Th) subsets that are vital for protection against diverse types of infection. However, the mechanisms employed by DCs to initiate Th2 responses, which are important for immunity to helminth infection as well as being a major contributor to allergic disease, remain poorly understood. We demonstrate a crucial role for methyl-CpG-binding domain-2 (Mbd2), a protein that links DNA methylation to repressive chromatin structure, in regulating DC gene expression and ability to promote Th2 immunity against either helminths or allergens. RNAs were extracted from murine (C57BL/6) Bone marrow-derived dendritic cells (BMDC) samples. Two groups of samples (three replicates each) were processed: (1) wild type, and (2) a homozygous knock-out of the Mbd2 locus.

2015-04-20 | E-GEOD-66096 | biostudies-arrayexpress

Detection of miRNAs in exosomes released by mouse immature and mature dendritic cells

Project description:Dendritic cells (DCs) are the most potent antigen (Ag)-presenting cells. Whereas immature DCs down-regulate T cell responses to induce/maintain immunological tolerance, mature DCs promote immunity. To amplify their functions, DCs communicate with neighboring DCs through soluble mediators, cell-to-cell contact and vesicle exchange. Transfer of nanovesicles (<100nm) derived from the endocytic pathway (termed exosomes) represents a novel mechanism of DC-to-DC communication. The facts that exosomes contain exosome-shuttle microRNAs (miRNAs), and DC functions can be regulated by exogenous miRNAs, suggest that DC-to-DC interactions could be mediated through exosome-shuttle miRNAs, an hypothesis that remains to be tested. Importantly, the mechanism of transfer of exosome-shuttle miRNAs from the exosome lumen to the cytosol of target cells is unknown. Here, we demonstrate that DCs release exosomes with different miRNAs depending on the maturation of the DCs. By visualizing spontaneous transfer of exosomes between DCs, we demonstrate that exosomes fused with the target DCs, the latter followed by release of the exosome content into the DC cytosol. Importantly, exosome-shuttle miRNAs are functional, as they repress target mRNAs of acceptor DCs. Our findings unveil a mechanism of transfer of exosome-shuttle miRNAs between DCs and its role as a means of communication and post-transcriptional regulation between DCs. The study has analyzed the microRNA content of 4 samples of immature exosomes, 4 samples of matures exosomes, 2 samples of immature bone-marrow-derived DCs, and 2 samples of mature bone marrow-derived DCs.

2011-10-24 | E-GEOD-33179 | biostudies-arrayexpress

A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells [ChIP-Seq]

Project description:Dendritic cells (DCs) direct CD4+ T cell differentiation into distinct T helper (Th) subsets that are vital for protection against diverse types of infection. However, the mechanisms employed by DCs to initiate Th2 responses, which are important for immunity to helminth infection as well as being a major contributor to allergic disease, remain poorly understood. We demonstrate a key role for methyl-CpG-binding domain-2 (Mbd2), a protein that links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function. In the absence of Mbd2, DCs displayed reduced phenotypic activation and a dramatically impaired ability to promote Th2 immunity against either helminths or allergens, while their induction of Th1/17 responses remained intact. These data reveal a novel epigenetic mechanism that is integral to DC promotion of CD4+ T cell responses, particularly in Th2 settings, and identify methyl-CpG-binding proteins and the genes that they control as potential therapeutic targets for type-2 inflammation.

2015-04-20 | GSE66198 | GEO

Proteome and phophoproteome analysis of distinct dendritic cell maturation states

Project description:Depending on their environment and their exposure to various factors, dendritic cells (DCs) exist in different activation and maturation states. The versatility of DCs allows them to shape the immune system towards an inflammatory or tolerant state depending on the antigens and the environment they encounter. In this study we aimed to provide a proteomic catalogue of differentially expressed and differentially phosphorylated proteins between distinct DC maturation states, brought about by bacteria that differ in their endotoxicity. To achieve this, we have performed unlabeled shotgun proteomics and phosphoproteomics on cell fractions obtained from murine bone marrow DC cultures. The symbiont B. vulgatus stimulation was used to obtain semi-mature DCs, and the pathobiont E. coli stimulation was used to obtain mature DCs. For both shotgun proteome and phosphoproteome analysis two biological replicates consisting of 8 mice were used. Each biological replicate were run as 3 technical replicates.

2017-11-27 | PXD003738 | Pride

A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells [gene expression]

2015-04-20 | GSE66096 | GEO

PDL2+, PDL2- and LPS treated PDL2- WT bone-marrow derived murine DCs

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2013-09-17 | E-GEOD-50898 | biostudies-arrayexpress

Modulation of murine bone marrow derived dendritic cells by IL-4

Project description:The archetypal Th2 cytokine interleukin 4 (IL-4) has previously been shown to alternatively activate dendritic cells (DCs) both in vitro and in vivo.To more fully understand the impact of IL-4 dependent alternative activation of DCs, we used mRNA microarrays to define their transcriptional profile. RNAs were extracted from bone marrow-derived dendritic cells (BMDCs). Two groups of samples were taken, with three biological replicates in each: control untreated, and treated with recombinant-IL4 (at 20 ng/ml).

2015-04-28 | E-GEOD-59868 | biostudies-arrayexpress

Membrane Vesicles of a Bacterial Mutualist Mediate Immune Regulation via Dendritic Cells

Project description:Microbial molecules have evolved to promote transient and/or permanent associations with mammals. Although numerous examples of secretion systems employed by pathogens have been described, mechanisms by which commensal bacteria export molecules during symbiosis remain unknown. The human gut mutualist Bacteroides fragilis produces a capsular polysaccharide (PSA) that directs host immune development. We reveal herein that outer membrane vesicles (OMVs) deliver PSA to dendritic cells (DCs), promoting regulatory T cells and inducing anti-inflammatory cytokines during protection from intestinal disease. In addition, we found that TLR2 signaling by DCs is required for OMV sensing. Following internalization into DCs and engagement of TLR2, OMVs initiate a gene expression program that results in IL-10 production by DCs. Although it is known that the outcome of PSA sensing by the immune system is Treg induction, nothing is known about the intracellular signaling pathway(s) activated by PSA within DCs. We analyzed the gene expression profile of DCs treated with OMVs to uncover factors that are expressed in a PSA-dependent, TLR2-dependent manner. Our findings demonstrate DC-induced protection from disease via OMV-delivery of a beneficial microbial molecule, uncovering a novel paradigm for inter-kingdom communication between the microbiota and mammals. RNA samples (1ug total RNA) from BMDCs were labeled with fluorescent dyes using the Quick Amp Labeling Kit (Agilent). Microarray (AgilentWhole Mouse Genome chip) hybridizations (65M-BM-0C for 16 hours) and washes were performed with Agilent reagents following standard protocols. Microarrays were analyzed using an Agilent DNA Microarray Scanner G2565CA, and data were acquired using Agilent's Feature Extraction Software version 10.1.1.1. Significant genes were selected based on p< 0.01 and fold change >2.0.

2012-07-22 | E-GEOD-39563 | biostudies-arrayexpress

Genome wide profiling of MBD2 binding

Project description:We show that in vivo MBD2 is mainly recruited to CpG island promoters that are highly methylated. We also report that MBD2 binds to a subset of CpG island promoters that are characterized by the presence of active histone marks and RNA polymerase II (Pol2). At such sites, MBD2 binds downstream of the transcription start site. Active promoters bound by MBD2 show low to medium gene expression levels and H3K36me3 deposition suggesting a putative role for MBD2 in blocking polymerase II (Pol2) elongation at these promoters. To gain further insight into the function of and epigenetic regulation by MBD2 we generated a tagged version of the protein and stably expressed it in the MCF-7 cell line. We mapped genome wide binding of MBD2 by ChIP sequencing (ChIP-seq) and together with base resolution whole genome bisulfite sequencing (WGBS) we were able to determine the methylation content and the role of methylation density at MBD2 enriched regions. We further dissected MBD2 binding properties, taking advantage of a large set of ChIP-seq data including active histone marks, RNA polymerase II (POL2) and strand specific RNA-seq.

2014-07-03 | E-GEOD-54693 | biostudies-arrayexpress

Distinct populations of CD11b+ IRF4+ dendritic cells drive Th2 responses in the small intestine and colon

Project description:We have identified the dendritic cell (DC) populations that are sufficient for the induction of T helper 2 (Th2) cell responses in the intestine against both live Trichuris muris worms, and inert Schistosoma mansoni eggs. Antigen-specific Th2 responses did not develop after deletion of IRF4 in DCs, yet IRF4-deficient DCs were not functionally affected. Instead, IRF4flox/flox CD11c-cre mice had fewer CD11b+ migrating DCs, and fewer DCs carrying parasite antigen from the intestine. Adoptive transfer of purified DCs from infected animals directly into intestinal afferent lymphatics enabled us to identify that CD11b+CD103+ DCs were central to the induction of Th2 responses in the small intestine, whereas CD11b+CD103- DCs were more important in the colon. Similarly, after pulsing with Schistosome egg antigen (SEA) in vitro, adoptively-transferred small intestinal or colonic DCs acquired the ability to induce SEA-specific Th2 responses. These data demonstrate a functional specialisation among intestinal DC populations in inducing Th2 responses, and elucidate the roles of IRF4 in this process.

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