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Suppression of inflammation by a synthetic histone mimic


Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression1,2,3,4. Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression5,6,7,8,9,10. Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by ‘mimicking’ acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.

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Figure 1: I-BET is a selective antagonist of BET proteins.
Figure 2: I-BET suppresses a specific subset of LPS-inducible genes.
Figure 3: Epigenetic profiles of genes suppressed or unaffected by I-BET in LPS-stimulated macrophages.
Figure 4: I-BET suppresses inflammation in vivo.

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Gene Expression Omnibus

Protein Data Bank

Data deposits

Crystal structure of the first bromodomain of human BRD4 in complex with I-BET inhibitor was deposited in the RCSB Protein Data Bank with PDB ID code 3P5O. Microarray and ChIP sequencing results were deposited in GEO with GEO accession codes GSE21764 and GSE21910, respectively.


  1. Medzhitov, R. & Horng, T. Transcriptional control of the inflammatory response. Nature Rev. Immunol. 9, 692–703 (2009)

    Article  CAS  Google Scholar 

  2. Smale, S. T. Selective transcription in response to an inflammatory stimulus. Cell 140, 833–844 (2010)

    Article  CAS  Google Scholar 

  3. Natoli, G. Control of NF-κB-dependent transcriptional responses by chromatin organization. Cold Spring Harb. Perspect. Biol. 1, a000224 (2009)

    Article  Google Scholar 

  4. Maniatis, T. & Reed, R. An extensive network of coupling among gene expression machines. Nature 416, 499–506 (2002)

    Article  ADS  CAS  Google Scholar 

  5. Hargreaves, D. C., Horng, T. & Medzhitov, R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138, 129–145 (2009)

    Article  CAS  Google Scholar 

  6. LeRoy, G., Rickards, B. & Flint, S. J. The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol. Cell 30, 51–60 (2008)

    Article  CAS  Google Scholar 

  7. Jang, M. K. et al. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol. Cell 19, 523–534 (2005)

    Article  CAS  Google Scholar 

  8. Yang, Z. et al. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol. Cell 19, 535–545 (2005)

    Article  CAS  Google Scholar 

  9. Taverna, S. D., Li, H., Ruthenburg, A. J., Allis, C. D. & Patel, D. J. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nature Struct. Mol. Biol. 14, 1025–1040 (2007)

    Article  CAS  Google Scholar 

  10. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001)

    Article  CAS  Google Scholar 

  11. Ruthenburg, A. J., Li, H., Patel, D. J. & Allis, C. D. Multivalent engagement of chromatin modifications by linked binding modules. Nature Rev. Mol. Cell Biol. 8, 983–994 (2007)

    Article  CAS  Google Scholar 

  12. Huang, H. et al. Solution structure of the second bromodomain of Brd2 and its specific interaction with acetylated histone tails. BMC Struct. Biol. 7, 57 (2007)

    Article  Google Scholar 

  13. Liu, Y. et al. Structural basis and binding properties of the second bromodomain of Brd4 with acetylated histone tails. Biochemistry 47, 6403–6417 (2008)

    Article  CAS  Google Scholar 

  14. Vollmuth, F., Blankenfeldt, W. & Geyer, M. Structures of the dual bromodomains of the P-TEFb-activating protein Brd4 at atomic resolution. J. Biol. Chem. 284, 36547–36556 (2009)

    Article  CAS  Google Scholar 

  15. Gavrilin, M. A. et al. Pyrin critical to macrophage IL-1β response to Francisella challenge. J. Immunol. 182, 7982–7989 (2009)

    Article  CAS  Google Scholar 

  16. Hagen, F. S. et al. Expression and characterization of recombinant human acyloxyacyl hydrolase, a leukocyte enzyme that deacylates bacterial lipopolysaccharides. Biochemistry 30, 8415–8423 (1991)

    Article  CAS  Google Scholar 

  17. Huang, B., Yang, X. D., Zhou, M. M., Ozato, K. & Chen, L. F. Brd4 coactivates transcriptional activation of NF-κB via specific binding to acetylated RelA. Mol. Cell. Biol. 29, 1375–1387 (2009)

    Article  CAS  Google Scholar 

  18. Jiang, Y. W. et al. Mammalian mediator of transcriptional regulation and its possible role as an end-point of signal transduction pathways. Proc. Natl Acad. Sci. USA 95, 8538–8543 (1998)

    Article  ADS  CAS  Google Scholar 

  19. Denis, G. V. et al. Identification of transcription complexes that contain the double bromodomain protein Brd2 and chromatin remodeling machines. J. Proteome Res. 5, 502–511 (2006)

    Article  CAS  Google Scholar 

  20. Nishiyama, A., Dey, A., Miyazaki, J. & Ozato, K. Brd4 is required for recovery from antimicrotubule drug-induced mitotic arrest: preservation of acetylated chromatin. Mol. Biol. Cell 17, 814–823 (2006)

    Article  CAS  Google Scholar 

  21. Marshall, N. F., Peng, J., Xie, Z. & Price, D. H. Control of RNA polymerase II elongation potential by a novel carboxyl-terminal domain kinase. J. Biol. Chem. 271, 27176–27183 (1996)

    Article  CAS  Google Scholar 

  22. Sims, R. J., III, Belotserkovskaya, R. & Reinberg, D. Elongation by RNA polymerase II: the short and long of it. Genes Dev. 18, 2437–2468 (2004)

    Article  CAS  Google Scholar 

  23. Ramirez-Carrozzi, V. R. et al. Selective and antagonistic functions of SWI/SNF and Mi-2β nucleosome remodeling complexes during an inflammatory response. Genes Dev. 20, 282–296 (2006)

    Article  CAS  Google Scholar 

  24. Ramirez-Carrozzi, V. R. et al. A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell 138, 114–128 (2009)

    Article  CAS  Google Scholar 

  25. Lee, T. I., Johnstone, S. E. & Young, R. A. Chromatin immunoprecipitation and microarray-based analysis of protein location. Nature Protocols 1, 729–748 (2006)

    Article  CAS  Google Scholar 

  26. Goldberg, A. D. et al. Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140, 678–691 (2010)

    Article  CAS  Google Scholar 

  27. Rittirsch, D., Huber-Lang, M. S., Flierl, M. A. & Ward, P. A. Immunodesign of experimental sepsis by cecal ligation and puncture. Nature Protocols 4, 31–36 (2008)

    Article  Google Scholar 

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We would like to acknowledge R. Grimley and C. Patel for supplying FRET data and R. Woodward, C. Delves, E. Jones and P. Holmes for protein production. J. Witherington, N. Smithers, S. Baddeley, J. Seal and L. Cutler provided compound selectivity and pharmacokinetics data. G. Krysa, O. Mirguet and R. Gosmini contributed to the discovery, development and characterization of the compound. We thank R. Anthony and S. McCleary for assistance with animal models, R. Gejman for bioinformatics analysis of gene expression kinetics and A. Santana and T. Chapman for technical assistance. We would like to thank C. Nathan, R. Medzhitov, S. Rudensky and S. Smale for helpful discussions and S. Sampath for his contribution to the concept of ‘histone mimicry’. R.C. is supported by an NIH KL2 Career Development Award and I.M. is supported by the American Italian Cancer Foundation. K.L.J. is supported by the National Health and Medical Research Council of Australia and is currently a Rockefeller University Women in Science Fellow.

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Authors and Affiliations



E.N. identified, characterized and optimized the compound for in vivo experiments; K.L.J., U.S. and S.B. contributed equally to design, execution and analysis of in vitro and in vivo experiments. S.D. performed bioinformatics analysis of ChIP sequencing data; C.-w.C. performed crystallography, ITC, SPR and thermal shift assays; R.C. performed quantitative analysis of epigenetic states of the LPS-inducible genes; I.M. optimized BRD2 and BRD3 profiling of the LPS-inducible genes; P.W. performed bioinformatics analysis of gene expression in LPS-stimulated macrophages. H.C., J.W. and J.K. discovered, characterised and optimised the compound for in vivo experiments. C.M.R. was involved in studies of inflammatory responses. J.M.L., R.K.P. and K.L. contributed to the initiation and development of the studies on pharmacological targeting of proteins that recognize post-translationally modified histones. A.T. conceived and supervised this study, and wrote the final manuscript.

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Correspondence to Kevin Lee or Alexander Tarakhovsky.

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E.N., S.B., C.-w.C., P.W., H.C., J.W., J.K., J.M.L., R.K.P. and K.L. are employees of GlaxoSmithKline. Research support, excluding salaries to the members of The Rockefeller University, but including protein analysis and compound synthesizing equipment, supplies and other expense, was provided by GlaxoSmithKline.

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Nicodeme, E., Jeffrey, K., Schaefer, U. et al. Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119–1123 (2010).

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