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Proteomic dissection of LPS-inducible, PHF8-dependent secretome reveals novel roles of PHF8 in TLR4-induced acute inflammation and T cell proliferation.

Publication ,  Journal Article
Erdoğan, Ö; Xie, L; Wang, L; Wu, B; Kong, Q; Wan, Y; Chen, X
Published in: Scientific reports
April 2016

Endotoxin (LPS)-induced changes in histone lysine methylation contribute to the gene-specific transcription for control of inflammation. Still unidentified are the chromatin regulators that drive the transition from a transcriptional-repressive to a transcriptional-active chromatin state of pro-inflammatory genes. Here, using combined approaches to analyze LPS-induced changes in both gene-specific transcription and protein secretion to the extracellular compartment, we characterize novel functions of the lysine demethylase PHF8 as a pro-inflammatory, gene-specific chromatin regulator. First, in the LPS-induced, acute-inflamed macrophages, PHF8 knockdown led to both a reduction of pro-inflammatory factors and an increase in a transcriptional-repressive code (H3K9me2) written by the methyltransferase G9a. Through unbiased quantitative secretome screening we discovered that LPS induces the secretion of a cluster of PHF8-dependent, 'tolerizable' proteins that are related to diverse extracellular pathways/processes including those for the activation of adaptive immunity. Specifically, we determined that PHF8 promotes T-cell activation and proliferation, thus providing the first link between the epigenetic regulation of inflammation and adaptive immunity. Further, we found that, in the acute-inflamed macrophages, the acute-active PHF8 opposes the H3K9me1/2-writing activity of G9a to activate specific protein secretions that are suppressed by G9a in the endotoxin-tolerant cells, revealing the inflammatory-phenotypic chromatin drivers that regulate the gene-specific chromatin plasticity.

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Published In

Scientific reports

DOI

EISSN

2045-2322

ISSN

2045-2322

Publication Date

April 2016

Volume

6

Start / End Page

24833

Related Subject Headings

  • Transcription Factors
  • Toll-Like Receptor 4
  • RNA, Small Interfering
  • RNA Interference
  • RAW 264.7 Cells
  • Proteomics
  • Protein Phosphatase 2C
  • Phosphopeptides
  • NF-kappa B
  • Mice
 

Citation

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Erdoğan, Ö., Xie, L., Wang, L., Wu, B., Kong, Q., Wan, Y., & Chen, X. (2016). Proteomic dissection of LPS-inducible, PHF8-dependent secretome reveals novel roles of PHF8 in TLR4-induced acute inflammation and T cell proliferation. Scientific Reports, 6, 24833. https://doi.org/10.1038/srep24833
Erdoğan, Özgün, Ling Xie, Li Wang, Bing Wu, Qing Kong, Yisong Wan, and Xian Chen. “Proteomic dissection of LPS-inducible, PHF8-dependent secretome reveals novel roles of PHF8 in TLR4-induced acute inflammation and T cell proliferation.Scientific Reports 6 (April 2016): 24833. https://doi.org/10.1038/srep24833.
Erdoğan, Özgün, et al. “Proteomic dissection of LPS-inducible, PHF8-dependent secretome reveals novel roles of PHF8 in TLR4-induced acute inflammation and T cell proliferation.Scientific Reports, vol. 6, Apr. 2016, p. 24833. Epmc, doi:10.1038/srep24833.

Published In

Scientific reports

DOI

EISSN

2045-2322

ISSN

2045-2322

Publication Date

April 2016

Volume

6

Start / End Page

24833

Related Subject Headings

  • Transcription Factors
  • Toll-Like Receptor 4
  • RNA, Small Interfering
  • RNA Interference
  • RAW 264.7 Cells
  • Proteomics
  • Protein Phosphatase 2C
  • Phosphopeptides
  • NF-kappa B
  • Mice