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The journal of immunology : official journal of the American Association of Immunologists v.198 no.3, 2017년, pp.1297 - 1307   SCI SCIE
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Epigenetic and Transcriptional Regulation of IRAK-M Expression in Macrophages

Lyroni, Konstantina (Laboratory of Clinical Chemistry, Medical School, University of Crete, Heraklion 71003, Crete, Greece ); Patsalos, Andreas (Laboratory of Clinical Chemistry, Medical School, University of Crete, Heraklion 71003, Crete, Greece ); Daskalaki, Maria G. (Laboratory of Biochemistry, Medical School, University of Crete, Heraklion 71003, Crete, Greece ); Doxaki, Christina (and ); Soennichsen, Birte (Laboratory of Clinical Chemistry, Medical School, University of Crete, Heraklion 71003, Crete, Greece ); Helms, Mike (Cenix Bioscience GmbH, D01307 Dresden, Germany ); Liapis, Ioannis (Cenix Bioscience GmbH, D01307 Dresden, Germany ); Zacharioudaki, Vassiliki (Laboratory of Clinical Chemistry, Medical School, University of Crete, Heraklion 71003, Crete, Greece ); Kampranis, Sotirios C. (Laboratory of Clinical Chemistry, Medical School, University of Crete, Heraklion 71003, Crete, Greece ); Tsatsanis, Christos (Laboratory of Biochemistry, Medical School, University of Crete, Heraklion 71003, Crete, Greece );
  • 초록  

    During macrophage activation, expression of IL-1R–associated kinase (IRAK)-M is induced to suppress TLR-mediated responses and is a hallmark of endotoxin tolerance. Endotoxin tolerance requires tight regulation of genes occurring at the transcriptional and epigenetic levels. To identify novel regulators of IRAK-M, we used RAW 264.7 macrophages and performed a targeted RNA interference screen of genes encoding chromatin-modifying enzymes, signaling molecules, and transcription factors involved in macrophage activation. Among these, the transcription factor CCAAT/enhancer binding protein (C/EBP)β, known to be involved in macrophage inactivation, was necessary for the induction of IRAK-M expression. Chromatin immunoprecipitation showed that C/EBPβ was recruited to the IRAK-M promoter following LPS stimulation and was indispensable for IRAK-M transcriptional activation. Among histone 3–modifying enzymes, our screen showed that knockdown of the histone 3 lysine 27 (H3K27) methyltransferase and part of the polycomb recessive complex 2, enhancer of Zeste 2, resulted in IRAK-M overexpression. In contrast, knockdown of the H3K27 demethylase ubiquitously transcribed tetratricopeptide repeat X chromosome suppressed the induction of IRAK-M in response to LPS stimulation. Accordingly, we demonstrated that H3K27 on the IRAK-M promoter is trimethylated in unstimulated cells and that this silencing epigenetic mark is removed upon LPS stimulation. Our data propose a mechanism for IRAK-M transcriptional regulation according to which, in the naive state, polycomb recessive complex 2 repressed the IRAK-M promoter, allowing low levels of expression; following LPS stimulation, the IRAK-M promoter is derepressed, and transcription is induced to allow its expression.


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