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Molecular and Cellular Biology, April 2009, p. 1959-1971, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01862-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Chromatin-Specific Remodeling by HMGB1 and Linker Histone H1 Silences Proinflammatory Genes during Endotoxin Tolerance{triangledown}

Mohamed El Gazzar,1* Barbara K. Yoza,2 Xiaoping Chen,1 Benjamin A. Garcia,3 Nicolas L. Young,3 and Charles E. McCall1

Department of Internal Medicine, Section of Molecular Medicine,1 Department of General Surgery, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157,2 Department of Molecular Biology, Princeton University, Princeton, New Jersey 085443

Received 5 December 2008/ Accepted 12 January 2009

Epigenetic silencing of tumor necrosis factor alpha (TNF-{alpha}) and interleukin 1β (IL-1β) transcription occurs in blood leukocytes of animals and humans after the initiation of severe systemic inflammation (SSI). We previously reported that the epigenetic signature requires induction of NF-{kappa}B factor RelB, which directs histone H3K9 dimethylation, disrupts assembly of transcription activator NF-{kappa}B p65, and induces a sustained switch from the euchromatin to heterochromatin. Here, we report the novel findings that intracellular high mobility group box 1 protein (HMGB1) and nucleosome linker histone H1 protein are necessary components of endotoxin-mediated silencing of TNF-{alpha} in THP-1 human promonocytes. HMGB1 binds the TNF-{alpha} promoter during transcription silencing and promotes assembly of the repressor RelB. Depletion of HMGB1 by small interfering RNA results in dissociation of RelB from the promoter and partially restores TNF-{alpha} transcription. Histone H1, which typically displaces HMGB1 from nucleosomal DNA, also binds concomitantly with HMGB1 to the heterochromatin of the silenced TNF-{alpha} promoter. Combined knockdown of HMGB1 and H1 restores binding of the transcriptionally active NF-{kappa}B p65 and reestablishes TNF-{alpha} mRNA levels. Chromatin reimmunoprecipitation experiments demonstrate that HMGB1 and H1 are likely recruited to TNF-{alpha} sequences independently and that their binding correlates with histone H3K9 dimethylation, as inhibition of histone methylation blocks HMGB1 and H1 binding. Moreover, HMGB1- and H1-mediated chromatin modifications are gene specific during endotoxin silencing in that they also bind and repress acute proinflammatory IL-1β, while no binding nor repression of antiinflammatory I{kappa}B{alpha} is observed. Finally, we find that H1 and HMGB1 bind to the TNF-{alpha} a promoter in human leukocytes obtained from patients with SSI. We conclude proinflammatory HMGB1 and structural nucleosome linker H1 couple as a component of the epigenetic complex that silences acute proinflammatory TNF-{alpha} during the assembly of heterochromatin in the SSI phenotype.

* Corresponding author. Mailing address: Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. Phone: (336) 716-8622. Fax: (336) 716-1214. E-mail: melgazza{at}wfubmc.edu

{triangledown} Published ahead of print on 21 January 2009.

Molecular and Cellular Biology, April 2009, p. 1959-1971, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01862-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Chen, X., El Gazzar, M., Yoza, B. K., McCall, C. E. (2009). The NF-{kappa}B Factor RelB and Histone H3 Lysine Methyltransferase G9a Directly Interact to Generate Epigenetic Silencing in Endotoxin Tolerance. J. Biol. Chem. 284: 27857-27865 [Abstract] [Full Text]  
  • Khan, Z., Bloom, J. S., Garcia, B. A., Singh, M., Kruglyak, L. (2009). Protein quantification across hundreds of experimental conditions. Proc. Natl. Acad. Sci. USA 106: 15544-15548 [Abstract] [Full Text]  


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