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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.

ORGANISM(S): Mus musculus

PROVIDER: GSE66198 | GEO | 2015/04/20

SECONDARY ACCESSION(S): PRJNA276101

REPOSITORIES: GEO

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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. 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.

2015-04-20 | E-GEOD-66198 | biostudies-arrayexpress

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

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

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

2015-04-20 | GSE66096 | GEO

Role of interleukin-4 in the licensing of dendritic cells for the induction of Th2 responses [A]

Project description:T helper type 2 (Th2) responses are crucial for defense against infections by helminths and are responsible for the development of allergic reactions that can lead to severe clinical disorders, such as asthma or anaphylaxis, and ultimately to death. The induction of Th2 responses requires a specific activation process, triggered by specialized dendritic cells (DCs), by which naive CD4+ Th0 cells acquire the capacity to produce Th2 cytokines. However, the mechanistic basis of the functional specialization enabling DCs for the initiation of Th2 responses has remained elusive. Here we show that interleukin-4 (IL-4), a cytokine produced by basophils, mast cells and Th2-polarized CD4+ T helper cells, exerting a crucial function during anti-helminths and allergic Th2 responses, has a key role in the licensing/conditioning of DCs for the induction of Th2 responses, by bloking their potential to produce Th1-driving cytokines, such as IL-12, IL-18 and IL-23. Microarray analyses (duplicates) were for two types of comparisons: 1. moDCs stimulated with LPS from Escherichia coli versus C-moDCs non stimulated (control). 2. moDCs stimulated with LPS from Escherichia coli in presence of IL4 versus C-moDCs non stimulated (control).

2014-02-19 | E-GEOD-39862 | biostudies-arrayexpress

Role of interleukin-4 in the licensing of dendritic cells for the induction of Th2 responses [B]

Project description:T helper type 2 (Th2) responses are crucial for defense against infections by helminths and are responsible for the development of allergic reactions that can lead to severe clinical disorders, such as asthma or anaphylaxis, and ultimately to death. The induction of Th2 responses requires a specific activation process, triggered by specialized dendritic cells (DCs), by which naive CD4+ Th0 cells acquire the capacity to produce Th2 cytokines. However, the mechanistic basis of the functional specialization enabling DCs for the initiation of Th2 responses has remained elusive. Here we show that interleukin-4 (IL-4), a cytokine produced by basophils, mast cells and Th2-polarized CD4+ T helper cells, exerting a crucial function during anti-helminths and allergic Th2 responses, has a key role in the licensing/conditioning of DCs for the induction of Th2 responses, by bloking their potential to produce Th1-driving cytokines, such as IL-12, IL-18 and IL-23. Microarray analyses (duplicates) were used to compared the transcriptional profile of monocyte-derived dendritic cells (moDCs) cultured with GM-CSF in the absence or presence of interleukin-4: IL4-moDCs versus C-moDCs.

2014-02-19 | E-GEOD-39858 | biostudies-arrayexpress

Role of interleukin-4 in the licensing of dendritic cells for the induction of Th2 responses [A]

2014-02-19 | GSE39862 | GEO

Role of interleukin-4 in the licensing of dendritic cells for the induction of Th2 responses [B]

2014-02-19 | GSE39858 | GEO

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.

2016-12-10 | GSE91381 | GEO

Methyl-CpG binding domain 2 (Mbd2) is an Epigenetic Regulator of Autism-Risk Genes and Cognition [RNA-seq]

Project description:The Methyl-CpG-Binding Domain Protein family has been implicated in neurodevelopmental disorders. The Methyl-CpG-binding domain 2 (Mbd2) binds methylated DNA and was shown to play an important role in cancer and immunity. Some evidence linked this protein to neurodevelopment. However, its exact role in neurodevelopment and brain function is mostly unknown. Here we show that Mbd2-deficiency in mice (Mbd2-/-) results in deficits in cognitive, social and emotional functions. Mbd2 binds regulatory DNA regions of neuronal genes in the hippocampus and loss of Mbd2 alters the expression of hundreds of genes with a robust down-regulation of neuronal gene pathways. Further, a genome-wide DNA methylation analysis found an altered DNA methylation pattern in regulatory DNA regions of neuronal genes in Mbd2-/- mice. Differentially expressed genes significantly overlap with gene-expression changes observed in brain of Autism Spectrum Disorder (ASD) individuals. Notably, down-regulated genes are significantly enriched for human ortholog ASD risk-genes. Observed hippocampal morphological abnormalities were similar to those found in individuals with ASD and ASD rodent models. Mbd2 knockdown partially recapitulates the behavioral phenotypes observed in Mbd2-/- mice. These findings suggest Mbd2 is a novel epigenetic regulator of genes that are associated with ASD in humans. Mbd2 loss causes behavioral alterations that resemble those found in ASD patients.

2023-06-22 | GSE128828 | GEO

Methyl-CpG binding domain 2 (Mbd2) is an Epigenetic Regulator of Autism-Risk Genes and Cognition [ChIP-seq]

2023-06-22 | GSE128703 | GEO

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