| G9a and HP1 couple histone and DNA methylation to TNFalpha transcription silencing during endotoxin tolerance. | |
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MedLine Citation:
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PMID: 18809684 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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TNFalpha gene expression is silenced in the endotoxin tolerant phenotype that develops in blood leukocytes after the initial activation phase of severe systemic inflammation or sepsis. The silencing phase can be mimicked in vitro by LPS stimulation. We reported that the TNFalpha transcription is disrupted in endotoxin tolerant THP-1 human promonocyte due to changes in transcription factor binding and enrichment with histone H3 dimethylated on lysine 9 (H3K9). Here we show that the TNFalpha promoter is hypermethylated during endotoxin tolerance and that H3K9 methylation and DNA methylation interact to silence TNFalpha expression. Chromatin immunoprecipitation and RNA interference analysis demonstrated that, in tolerant cells, TNFalpha promoter is bound by the H3K9 histone methyltransferase G9a which dimethylates H3K9 and creates a platform for HP1 binding, leading to the recruitment of the DNA methyltransferase Dnmt3a/b and an increase in promoter CpG methylation. Knockdown of HP1 resulted in a decreased Dnmt3a/b binding, sustained G9a binding, and a modest increase in TNFalpha transcription, but had no effect on H3K9 dimethylation. In contrast, G9a knockdown-disrupted promoter silencing and restored TNFalpha transcription in tolerant cells. This correlated with a near loss of H3K9 dimethylation, a significant decrease in HP1 and Dnmt3a/b binding and promoter CpG methylation. Our results demonstrate a central role for G9a in this process and suggest that histone methylation and DNA methylation cooperatively interact via HP1 to silence TNFalpha expression during endotoxin tolerance and may have implication for proinflammatory gene silencing associated with severe systemic inflammation. |
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Authors:
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Mohamed El Gazzar; Barbara K Yoza; Xiaoping Chen; Jean Hu; Gregory A Hawkins; Charles E McCall |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2008-09-22 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 283 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2008 Nov |
Date Detail:
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Created Date: 2008-11-17 Completed Date: 2009-01-22 Revised Date: 2010-09-21 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 32198-208 Citation Subset: IM |
Affiliation:
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Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA. melgazzar@wfubmc.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Chromosomal Proteins, Non-Histone
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physiology* CpG Islands DNA Methylation Endotoxins / metabolism* Gene Silencing* Histocompatibility Antigens / physiology* Histone-Lysine N-Methyltransferase / physiology* Histones / chemistry Humans Inflammation Lipopolysaccharides / metabolism Promoter Regions, Genetic RNA Interference Transcription, Genetic* Tumor Necrosis Factor-alpha / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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R01AI-065791/AI/NIAID NIH HHS; R01AI-09169/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Chromosomal Proteins, Non-Histone; 0/Endotoxins; 0/Histocompatibility Antigens; 0/Histones; 0/Lipopolysaccharides; 0/Tumor Necrosis Factor-alpha; 107283-02-3/heterochromatin-specific nonhistone chromosomal protein HP-1; EC 2.1.1.43/EHMT2 protein, human; EC 2.1.1.43/Histone-Lysine N-Methyltransferase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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