Abstract
Members of the NF-κB family of transcription factors function as dominant regulators of inducible gene expression in almost all cell types in response to a broad range of stimuli, with particularly important roles in coordinating both innate and adaptive immunity. This review summarizes the present knowledge and recent progress toward elucidating the numerous regulatory layers that confer target-gene selectivity in response to an NF-κB-inducing stimulus.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Sen, R. & Baltimore, D. Inducibility of κ immunoglobulin enhancer-binding protein NF-κB by a posttranslational mechanism. Cell 47, 921–928 (1986).
Ghisletti, S. et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity 32, 317–328 (2010).
Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).
Saccani, S. & Natoli, G. Dynamic changes in histone H3 Lys 9 methylation occurring at tightly regulated inducible inflammatory genes. Genes Dev. 16, 2219–2224 (2002).
De Santa, F. et al. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130, 1083–1094 (2007).
De Santa, F. et al. Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J. 28, 3341–3352 (2009).
van Essen, D., Zhu, Y. & Saccani, S. A feed-forward circuit controlling inducible NF-κB target gene activation by promoter histone demethylation. Mol. Cell 39, 750–760 (2010).
Fan, W. et al. FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. EMBO J. 29, 4223–4236 (2010).
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).
De Santa, F. et al. A large fraction of extragenic RNA pol II transcription sites overlap enhancers. PLoS Biol. 8, e1000384 (2010).
Chen, L.L. & Carmichael, G.G. Decoding the function of nuclear long non-coding RNAs. Curr. Opin. Cell Biol. 22, 357–364 (2010).
Agalioti, T. et al. Ordered recruitment of chromatin modifying and general transcription factors to the IFN-β promoter. Cell 103, 667–678 (2000).
Panne, D., Maniatis, T. & Harrison, S.C. Crystal structure of ATF-2/c-Jun and IRF-3 bound to the interferon-β enhancer. EMBO J. 23, 4384–4393 (2004).
Panne, D., Maniatis, T. & Harrison, S.C. An atomic model of the interferon-β enhanceosome. Cell 129, 1111–1123 (2007).
Perkins, N.D. Post-translational modifications regulating the activity and function of the nuclear factor κ B pathway. Oncogene 25, 6717–6730 (2006).
Zhong, H., Voll, R.E. & Ghosh, S. Phosphorylation of NF-κB p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the co-activator CBP/p300. Mol. Cell 1, 661–671 (1998).
Zhong, H., May, M.J., Jimi, E. & Ghosh, S. Phosphorylation of nuclear NF-κB governs its association with either HDAC-1 or CBP/p300: a mechanism for regulating the transcriptional activity of NF-κB. Mol. Cell 9, 625–636 (2002).
Dong, J., Jimi, E., Zhong, H., Hayden, M.S. & Ghosh, S. Epigenetic regulation of NF-κB dependent gene expression. Genes Dev. 22, 1159–1173 (2008).
Levy, D. et al. Lysine methylation of the NF-κB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-κB signaling. Nat. Immunol. 12, 29–36 (2011).
Oeckinghaus, A., Hayden, M.S. & Ghosh, S. Cross-talk in NF-κB signaling pathways. Nat. Immunol. 12, 695–708 (2011).
Amir-Zilberstein, L. et al. Differential regulation of NF-κB by elongation factors is determined by core promoter type. Mol. Cell. Biol. 27, 5246–5259 (2007).
Hargreaves, D.C., Horng, T. & Medzhitov, R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138, 129–145 (2009).
Ghosh, S., May, M.J. & Kopp, E.B. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16, 225–260 (1998).
Hoffmann, A., Natoli, G. & Ghosh, G. Transcriptional regulation via the NF-κB signaling module. Oncogene 25, 6706–6716 (2004).
Vallabhapurapu, S. & Karin, M. Regulation and function of NF-κB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693–733 (2009).
Hoffmann, A. & Baltimore, D. Circuitry of NF-κB signaling. Immunol. Rev. 210, 171–186 (2006).
Sen, R. & Smale, S.T. Selectivity of the NF-κB response. Cold Spr. Harb. Perspect. Biol. 2, a000257 (2010).
Ashall, L. et al. Pulsatile stimulation determines timing and specificity of NF-κB-dependent transcription. Science 324, 242–246 (2009).
Tay, S. et al. Single-cell NF-κB dynamics reveal digital activation and analog information processing. Nature 466, 267–271 (2010).
Lee, T.K. & Covert, M.W. High-throughput single-cell NF-κB dynamics. Curr. Opin. Genet. Dev. 20, 677–683 (2010).
Paszek, P., Jackson, D.A. & White, M.R. Oscillatory control of signaling molecules. Curr. Opin. Genet. Dev. 20, 670–676 (2010).
Wang, Y. et al. Interactions among oscillatory pathways in NF-κB signaling. BMC Syst. Biol. 5, 23 (2011).
Ruland, J. Return to homeostasis: downregulation of NF-κB responses. Nat. Immunol. 12, 709–714 (2011).
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).
Barish, G.D. et al. Bcl-6 and NF-κB cistromes mediate opposing regulation of the innate immune response. Genes Dev. 24, 2760–2765 (2010).
Hao, S. & Baltimore, D. The stability of mRNA influences the temporal order of the induction of genes encoding inflammatory molecules. Nat. Immunol. 10, 281–288 (2009).
O'Connell, R.M., Rao, D.S., Chaudhuri, A.A. & Baltimore, D. Physiological and pathological roles for microRNAs in the immune system. Nat. Rev. Immunol. 10, 111–122 (2010).
Anderson, P. Post-transcriptional regulons coordinate the initiation and resolution of inflammation. Nat. Rev. Immunol. 10, 24–35 (2010).
Foster, S.L. & Medzhitov, R. Gene-specific control of the TLR-induced inflammatory response. Clin. Immunol. 130, 7–15 (2009).
Medzhitov, R. & Horng, T. Transcriptional control of the inflammatory response. Nat. Rev. Immunol. 9, 692–703 (2009).
Smale, S.T. Selective transcription in response to an inflammatory stimulus. Cell 140, 833–844 (2010).
Natoli, G. Maintaining cell identity through global control of genomic organization. Immunity 33, 12–24 (2010).
Natoli, G., Ghisletti, S. & Barozzi, I. The genomic landscapes of inflammation. Genes Dev. 25, 101–106 (2011).
Smale, S.T. Pioneer factors in embryonic stem cells and differentiation. Curr. Opin. Genet. Dev. 20, 519–526 (2010).
Gualdi, R. et al. Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev. 10, 1670–1682 (1996).
Kontaraki, J., Chen, H.H., Riggs, A. & Bonifer, C. Chromatin fine structure profiles for a developmentally regulated gene: reorganization of the lysozyme locus before trans-activator binding and gene expression. Genes Dev. 14, 2106–2122 (2000).
Zaret, K.S. et al. Pioneer factors, genetic competence, and inductive signaling: programming liver and pancreas progenitors from the endoderm. Cold Spring Harb. Symp. Quant. Biol. 73, 119–126 (2008).
Scott, E.W., Simon, M.C., Anastasi, J. & Singh, H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science 265, 1573–1577 (1994).
Schebesta, A. et al. Transcription factor Pax5 activates the chromatin of key genes involved in B cell signaling, adhesion, migration, and immune function. Immunity 27, 49–63 (2007).
Lin, Y.C. et al. A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nat. Immunol. 11, 635–643 (2010).
Treiber, T. et al. Early B cell factor 1 regulates B cell gene networks by activation, repression, and transcription- independent poising of chromatin. Immunity 32, 714–725 (2010).
Heintzman, N.D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311–318 (2007).
de Laat, W. & Grosveld, F. Spatial organization of gene expression: the active chromatin hub. Chromosome Res. 11, 447–459 (2003).
Zhou, L. et al. An inducible enhancer required for Il12b promoter activity in an insulated chromatin environment. Mol. Cell. Biol. 27, 2698–2712 (2007).
Xu, J. et al. Pioneer factor interactions and unmethylated CpG dinucleotides mark silent tissue-specific enhancers in embryonic stem cells. Proc. Natl. Acad. Sci. USA 104, 12377–12382 (2007).
Xu, J. et al. Transcriptional competence and the active marking of tissue-specific enhancers by defined transcription factors in embryonic and induced pluripotent stem cells. Genes Dev. 23, 2824–2838 (2009).
Nicodeme, E. et al. Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119–1123 (2010).
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).
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).
Yang, Z. et al. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol. Cell 19, 535–545 (2005).
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).
Yang, X.D. et al. Negative regulation of NF-κB action by Set9-mediated lysine methylation of the RelA subunit. EMBO J. 28, 1055–1066 (2009).
Ea, C.K. & Baltimore, D. Regulation of NF-κB activity through lysine monomethylation of p65. Proc. Natl. Acad. Sci. USA 106, 18972–18977 (2009).
Yang, X.D., Tajkhorshid, E. & Chen, L.F. Functional interplay between acetylation and methylation of the RelA subunit of NF-κB. Mol. Cell. Biol. 30, 2170–2180 (2010).
Leung, T.H., Hoffmann, A. & Baltimore, D. One nucleotide in a κB site can determine cofactor specificity for NF-κB dimers. Cell 118, 453–464 (2004).
van Essen, D., Engist, B., Natoli, G. & Saccani, S. Two modes of transcriptional activation at native promoters by NF-κB p65. PLoS Biol. 7, e73 (2009).
Yamamoto, M. & Takeda, K. Role of nuclear IκB proteins in the regulation of host immune responses. J. Infect. Chemother. 14, 265–269 (2008).
Wan, F. et al. Ribosomal protein S3: a KH domain subunit in NF-κB complexes that mediates selective gene regulation. Cell 131, 927–939 (2007).
Basehoar, A.D., Zanton, S.J. & Pugh, B.F. Identification and distinct regulation of yeast TATA box-containing genes. Cell 116, 699–709 (2004).
Tachibana, M. et al. Histone methyltransferase G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3–K9. Genes Dev. 19, 815–826 (2005).
Duran, A., Diaz-Meco, M.T. & Moscat, J. Essential role of RelA Ser311 phosphorylation by ζPKC in NF-κB transcriptional activation. EMBO J. 22, 3910–3918 (2003).
Ben-Neriah, Y. & Karin, M. Inflammation meets cancer, with NF-κB as the matchmaker. Nat. Immunol. 12, 715–723 (2011).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no competing financial interests.
Rights and permissions
About this article
Cite this article
Smale, S. Hierarchies of NF-κB target-gene regulation. Nat Immunol 12, 689–694 (2011). https://doi.org/10.1038/ni.2070
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni.2070
This article is cited by
-
Salmonella enterica serovar Typhi influences inflammation and autophagy in macrophages
Brazilian Journal of Microbiology (2022)
-
Cancer gene therapy by NF-κB-activated cancer cell-specific expression of CRISPR/Cas9 targeting telomeres
Gene Therapy (2020)
-
Myocardin-Related Transcription Factor A Mediates LPS-Induced iNOS Transactivation
Inflammation (2020)
-
Miltefosine increases macrophage cholesterol release and inhibits NLRP3-inflammasome assembly and IL-1β release
Scientific Reports (2019)
-
Functional domains of SP110 that modulate its transcriptional regulatory function and cellular translocation
Journal of Biomedical Science (2018)