Dendritic cell-associated miRNAs are modulated via chromatin remodeling in response to different environments.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, P. R. China.
Shiyue
S
Mei
Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, P. R. China.
Yuanhang
Y
Liu
Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, P. R. China.
Yue
Y
Bao
Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, P. R. China.
Yuan
Y
Zhang
Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, P. R. China.
Siping
S
Min
Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, P. R. China.
Yifei
Y
Liu
Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, P. R. China.
Yun
Y
Huang
Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, P. R. China.
Xidi
X
Yuan
Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, P. R. China.
Yue
Y
Feng
Department of Biochemistry, College of Life Science, Nankai University, Tianjin, P. R. China.
Jiandang
J
Shi
Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, P. R. China; Key Laboratory of Bioactive Materials, Ministry of Education, Tianjin, P. R. China.
Rongcun
R
Yang
D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D044127:Epigenesis, Genetic / Q000235:genetics*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics*; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D015415:Biomarkers; D006657:Histones; D008070:Lipopolysaccharides; D035683:MicroRNAs; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta