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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.

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

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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).

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