Global mapping of H3K4me3 and H3K27me3 reveals chromatin state-based regulation of human monocyte-derived dendritic cells in different environments

Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China.
Genes and immunity (Impact Factor: 2.91). 01/2012; 13(4):311-20. DOI: 10.1038/gene.2011.87
Source: PubMed


Depending on the environment, dendritic cells (DCs) may become active or tolerogenic, but little is known about whether heritable epigenetic modifications are involved in these processes. Here, we have found that epigenetic histone modifications can regulate the differentiation of human monocyte-derived DCs (moDCs) into either activated or tolerized DCs. The inhibition or silencing of methyltransferases or methylation-associated factors affects the expression of multiple genes. Genome mapping of transforming growth factor (TGF-β)- or lipopolysaccharide (LPS)-associated H3K4 trimethylation (H3K4me3) and H3K27 trimethylation (H3K27me3) demonstrated the presence of histone modification of gene expression in human TGF-β- or LPS-conditioned moDCs. Although the upregulated or downregulated genes were not always associated with H3K4me3 and/or H3K27me3 modifications in TGF-β-conditioned (tolerized) or LPS-conditioned (activated) moDCs, some of these genes may be regulated by the increased and/or decreased H3K4me3 or H3K27me3 levels or by the alteration of these epigenetic marks, especially in TGF-β-conditioned moDCs. Thus, our results suggested that the differentiation and function of moDCs in tumor and inflammation environments are associated with the modification of the H3K4me3 and K3K27me3 epigenetic marks.

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    • "ChIP (chromatin immunoprecipitation) and ChIP-seq (chromatin immunoprecipitation followed by high throughput sequencing) were performed by the Research & Cooperation Division of BGI-Shengzhen, China, as previously described [27]. The specificity of the immunoprecipitation was confirmed by qRT-PCR analysis of known genes; namely, GAPDH (which encodes transcriptionally active euchromatin), human MYOD1 (encoding transcriptionally inactive euchromatin) and human SAT2 (encoding heterochromatin). "
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    ABSTRACT: Epigenetic modification plays a critical role in regulating gene expression. To understand how epigenetic modification alters miRNA expression in monocyte-derived dendritic cells (moDCs) in different environments, we analyzed the connections between H3K4me3 and H3K27me3 modification and the expression of miRNAs in LPS- and TGF-β-conditioned moDCs. In moDCs, H3K4me3 modification was strongly associated with the expression of activating miRNAs, whereas H3K27me3 was related to repressive miRNAs. The regulation of miRNA expression by H3K4me3 and H3K27me3 was further confirmed by silencing or inhibiting methyltransferases or methylation-associated factors in LPS- and TGF-β-conditioned moDCs. siRNAs targeting H3K4me3-associated mixed lineage leukemia (MLL) and retinoblastoma binding protein 5 (RBBP5) reduced H3K4me3 enrichment and downregulated miRNA expression; conversely, silencing H3K27me3-associated enhancer of zeste homolog 2 (EZH2) and embryonic ectoderm development (EED) genes upregulated the DC-associated miRNAs. However, LPS-mediated miRNAs were often associated with H3K4me3 redistribution from the transcription start site (TSS) to the miRNA-coding region. Silencing LPS-associated NF-κB p65 and CBP/p300 not only inhibited H3K4m3 redistribution but also reduced miRNA expression. LPS-upregulated RBBP4 and RBBP7, which are involved in chromatin remodeling, also affected the redistribution of H3K4me3 and reduced the expression of miRNAs. In LPS- and TGF-β-conditioned moDCs, miRNAs may be modulated not only by H3K4m3 and H3K27me3 modification but also by redistribution of H3K4me3 around the transcriptional start site of miRNAs. Thus, H3K4me3 and H3K27me3 epigenetic modification may play an important role in regulating DC differentiation and function in the presence of tumor or inflammatory environments.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "We found that, in both organs and at both ages, the histone mark H3K4me3 was associated with high levels of gene expression, and H3K27me3 was associated with low levels of expression. These associations are similar to associations identified in other biological systems, including human embryonic stem cells differentiation [22]–[24], erythroid cells development [8], thyroid hormone (T3)-dependent metamorphosis [25], and dendritic cells activation [26]. Our findings suggest that this general concept – that H3K4me3 is associated with active transcription and H3K27me3 is associated with gene silencing – applies also to postnatal tissues in vivo. "
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