Dendritic Cell-Associated miRNAs Are Modulated via Chromatin Remodeling in Response to Different Environments

Shiyue Mei,Siping Min,Yifei Liu,Rongcun Yang,Xidi Yuan,Yue Feng,Yue Bao,Yuanhang Liu,Yuan Zhang,Jiandang Shi,Yun Huang,Kithiganahalli N Balaji

doi:10.1371/journal.pone.0090231

Shiyue Mei, Siping Min + Show 10 more

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https://doi.org/10.1371/journal.pone.0090231

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Abstract

IntroductionEpigenetic 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.ResultsIn 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.ConclusionIn 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.

Highlights

Epigenetic modification plays a critical role in regulating gene expression
H3K4me3 modification is associated with active miRNAs, whereas repressive miRNAs are related to H3K27me3 in monocyte-derived dendritic cells (moDCs)
We revealed the epigenetic features presented during moDC differentiation, and generated global maps of H3K4me3 and H3K27me3 modification in three cell types using the ChIP-Seq approach [27]

Summary

Introduction

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 H3K4me and H3K27me modification and the expression of miRNAs in LPS- and TGF-bconditioned moDCs. MiRNAs have emerged as key post-transcriptional regulators of gene expression in mammals [2], with each miRNA targeting dozens or possibly hundreds of mRNAs. More than 1000 miRNAs are encoded in the mammalian genome. The diverse functions of DCs in immune regulation depend on the heterogeneity of DC subsets and on their functional plasticity [6,7,8,9]. Upon exposure to TGF-b, DCs become tolerogenic In this way, they suppress T-cell alloreactivity [13] and induce Th2 or T regulatory responses [7,12]. More than 100 miRNAs are selectively expressed in adaptive and innate immune cells [14]. Because DC function depends on the cellular concentration of miRNA, the regulation of miRNA expression and abundance during ontogeny is not completely clear

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