Key points are not available for this paper at this time.
The interplay of transcription factors, histone modifiers, and DNA modification can alter chromatin structure that epigenetically controls gene transcription. During severe systemic inflammatory (SSI), the generation of facultative heterochromatin from euchromatin reversibly silences transcription of a set of acute proinflammatory genes. This gene-specific silencing is a salient feature of the endotoxin tolerant phenotype that is found in blood leukocytes of SSI patients and in a human THP-1 cell model of SSI. We previously reported that de novo induction of the NF-κB transcription factor RelB by endotoxin activation is necessary and sufficient for silencing transcription of acute proinflammatory genes in the endotoxin tolerant SSI phenotype. Here, we examined how RelB silences gene expression and found that RelB induces facultative heterochromatin formation by directly interacting with the histone H3 lysine 9 methyltransferase G9a. We found that heterochromatin protein 1 (HP1) and G9a formed a complex at the interleukin-1β promoter that is dependent on the Rel homology domain (RHD) of RelB. RelB knockdown disassociated the complex and reversed transcription silencing. We also observed that whereas RelB chromatin binding was independent of G9a, RelB transcriptional silencing required G9a accumulation at the silenced promoter. Binding between RelB and G9a was confirmed by glutathione S-transferase pulldown in vitro and coimmunoprecipitation in vivo. These data provide novel insight into how RelB is required to initiate silencing in the phenotype associated with severe systemic inflammation in humans, a disease with major morbidity and mortality. The interplay of transcription factors, histone modifiers, and DNA modification can alter chromatin structure that epigenetically controls gene transcription. During severe systemic inflammatory (SSI), the generation of facultative heterochromatin from euchromatin reversibly silences transcription of a set of acute proinflammatory genes. This gene-specific silencing is a salient feature of the endotoxin tolerant phenotype that is found in blood leukocytes of SSI patients and in a human THP-1 cell model of SSI. We previously reported that de novo induction of the NF-κB transcription factor RelB by endotoxin activation is necessary and sufficient for silencing transcription of acute proinflammatory genes in the endotoxin tolerant SSI phenotype. Here, we examined how RelB silences gene expression and found that RelB induces facultative heterochromatin formation by directly interacting with the histone H3 lysine 9 methyltransferase G9a. We found that heterochromatin protein 1 (HP1) and G9a formed a complex at the interleukin-1β promoter that is dependent on the Rel homology domain (RHD) of RelB. RelB knockdown disassociated the complex and reversed transcription silencing. We also observed that whereas RelB chromatin binding was independent of G9a, RelB transcriptional silencing required G9a accumulation at the silenced promoter. Binding between RelB and G9a was confirmed by glutathione S-transferase pulldown in vitro and coimmunoprecipitation in vivo. These data provide novel insight into how RelB is required to initiate silencing in the phenotype associated with severe systemic inflammation in humans, a disease with major morbidity and mortality. Inflammation is an evolutionarily conserved stereotypic stress response primarily orchestrated by temporal alterations in gene expression, with important contributions from complement, coagulation, and neurogenic processes (1Hotchkiss R.S. Karl I.E. N. Engl. J. Med. 2003; 348: 138-150Crossref PubMed Scopus (3219) Google Scholar, 2Riedemann N.C. Guo R.F. Ward P.A. J. Clin. Invest. 2003; 112: 460-467Crossref PubMed Scopus (559) Google Scholar). The genetic information encoded to generate inflammation regulates distinct functional sets of genes, including pro- and anti-inflammatory modifiers, directors of cell death, and mediators of cell respiration and metabolism (3McCall C.E. Yoza B.K. Am. J. Respir. Crit. Care Med. 2007; 175: 763-767Crossref PubMed Scopus (71) Google Scholar). The initiating stage of virtually all inflammation depends on sensory receptors coupled to intracellular signals that activate the immunity master regulator NF-κB to generate p65 and p50 transactivating heterodimers at euchromatin promoters of a set of early response proinflammatory genes. When spread throughout the circulation, this early stage may precipitate the extreme stress response of severe systemic inflammation (SSI). 4The abbreviations used are: SSIsevere systemic inflammationHP1heterochromatin protein 1IPimmunoprecipitationChIPchromatin immunoprecipitationGSTglutathione S-transferaseH3K9histone H3 lysine 9HMGB1high mobility group box protein 1IL-1βinterleukin 1βLPSlipopolysaccharide endotoxinRHDRel homology domainTLR4Toll-like receptor 4TNFαtumor necrosis factor αHAhemagglutininsiRNAsmall interfering RNA. Later stages of inflammation reprogramming often require protein synthesis and induce expression of distinct sets of genes with anti-inflammatory, survival, and energy regulation (4Cobb J.P. Buchman T.G. Karl I.E. Hotchkiss R.S. Surg. Infect. (Larchmt). 2000; 1: 207-215Crossref PubMed Scopus (35) Google Scholar, 5Ramirez-Carrozzi V.R. Nazarian A.A. Li C.C. Gore S.L. Sridharan R. Imbalzano A.N. Smale S.T. Genes Dev. 2006; 20: 282-296Crossref PubMed Scopus (350) Google Scholar). Recent data in humans from our laboratory and in animals from others highlight the role of epigenetics in regulating gene expression in the SSI phenotype (6Chan C. Li L. McCall C.E. Yoza B.K. J. Immunol. 2005; 175: 461-468Crossref PubMed Scopus (134) Google Scholar, 7El Gazzar M. Yoza B.K. Hu J.Y. Cousart S.L. McCall C.E. J. Biol. Chem. 2007; 282: 26857-26864Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 8El Gazzar M. Yoza B.K. Chen X. Hu J. Hawkins G.A. McCall C.E. J. Biol. Chem. 2008; 283: 32198-32208Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 9El Gazzar M. Yoza B.K. Chen X. Garcia B.A. Young N.L. McCall C.E. Mol. Cell. Biol. 2009; 29: 1959-1971Crossref PubMed Scopus (120) Google Scholar, 10Foster S.L. Hargreaves D.C. Medzhitov R. Nature. 2007; 447: 972-978Crossref PubMed Scopus (924) Google Scholar, 11Wen H. Dou Y. Hogaboam C.M. Kunkel S.L. Blood. 2008; 111: 1797-1804Crossref PubMed Scopus (146) Google Scholar). These epigenetic events provide specificity and plasticity among distinct sets of genes and depend on varied chromatin structure and modifications rather than distinct signaling pathways. severe systemic inflammation heterochromatin protein 1 immunoprecipitation chromatin immunoprecipitation glutathione S-transferase histone H3 lysine 9 high mobility group box protein 1 interleukin 1β lipopolysaccharide endotoxin Rel homology domain Toll-like receptor 4 tumor necrosis factor α hemagglutinin small interfering RNA. Chromatin exists in structural forms that provide access of DNA to transcription factors in responsive euchromatin and mask access to the transcriptional apparatus in compacted heterochromatin (12Kouzarides T. Cell. 2007; 128: 693-705Abstract Full Text Full Text PDF PubMed Scopus (8087) Google Scholar). Facultative heterochromatin defines chromatin that can switch between open euchromatin and compacted heterochromatin (13Trojer P. Reinberg D. Mol. Cell. 2007; 28: 1-13Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar). The mechanisms that control compaction and de-compaction of facultative heterochromatin to influence phenotypes through epigenetic control of gene expression are poorly defined but involve the cooperative interplay of transcription factors and modifiers of nucleosomal histones and DNA (12Kouzarides T. Cell. 2007; 128: 693-705Abstract Full Text Full Text PDF PubMed Scopus (8087) Google Scholar, 14Li B. Carey M. Workman J.L. Cell. 2007; 128: 707-719Abstract Full Text Full Text PDF PubMed Scopus (2684) Google Scholar). Regulation of chromatin structure through covalent and non-covalent histone modifications is critical for epigenetically regulating gene expression across the genome (15Ko M. Sohn D.H. Chung H. Seong R.H. Mutat. Res. 2008; 647: 59-67Crossref PubMed Scopus (36) Google Scholar). Histone lysine methylation participates in various chromatin-associating functions, including transcriptional regulation, heterochromatin formation, DNA repair, and recombination (16Kim J.K. Samaranayake M. Pradhan S. Cell. Mol. Life Sci. 2008; 66: 596-612Crossref Scopus (340) Google Scholar, 17Akbarian S. Huang H.S. Biol. Psychiatry. 2009; 65: 198-203Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). G9a is a major mammalian methyltransferase responsible for mono- and dimethylation of histone H3K9 at euchromatin regions (18Tachibana M. Ueda J. Fukuda M. Takeda N. Ohta T. Iwanari H. Sakihama T. Kodama T. Hamakubo T. Shinkai Y. Genes Dev. 2005; 19: 815-826Crossref PubMed Scopus (610) Google Scholar). Dimethylated H3K9 contributes to binding of heterochromatin protein 1 (HP1) and transition of accessible (open) euchromatin to compacted (closed) and transcriptionally silenced facultative heterochromatin (13Trojer P. Reinberg D. Mol. Cell. 2007; 28: 1-13Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar). We and others reported that epigenetic alterations generate gene-specific control of SSI by Toll-like receptor 4 (TLR4) induces chromatin modifications in blood leukocytes and lung dendritic cells (6Chan C. Li L. McCall C.E. Yoza B.K. J. Immunol. 2005; 175: 461-468Crossref PubMed Scopus (134) Google Scholar, 7El Gazzar M. Yoza B.K. Hu J.Y. Cousart S.L. McCall C.E. J. Biol. Chem. 2007; 282: 26857-26864Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 8El Gazzar M. Yoza B.K. Chen X. Hu J. Hawkins G.A. McCall C.E. J. Biol. Chem. 2008; 283: 32198-32208Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 9El Gazzar M. Yoza B.K. Chen X. Garcia B.A. Young N.L. McCall C.E. Mol. Cell. Biol. 2009; 29: 1959-1971Crossref PubMed Scopus (120) Google Scholar, 10Foster S.L. Hargreaves D.C. Medzhitov R. Nature. 2007; 447: 972-978Crossref PubMed Scopus (924) Google Scholar, 11Wen H. Dou Y. Hogaboam C.M. Kunkel S.L. Blood. 2008; 111: 1797-1804Crossref PubMed Scopus (146) Google Scholar). These chromatin modifications are associated with reversibly silencing one class of genes, which includes proinflammatory mediators, and sustaining or accentuating transcription activation of other classes of genes, including anti-inflammatory and anti-microbial mediators (3McCall C.E. Yoza B.K. Am. J. Respir. Crit. Care Med. 2007; 175: 763-767Crossref PubMed Scopus (71) Google Scholar). The epigenetic transcription silencing of acute proinflammatory genes requires G9a-dependent dimethylation of histone H3 lysine 9, recruitment of HP-1, CpG methylation of DNA, and assembly of H1 linker histone and high mobility group Box 1 (HMGB1) (7El Gazzar M. Yoza B.K. Hu J.Y. Cousart S.L. McCall C.E. J. Biol. Chem. 2007; 282: 26857-26864Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 8El Gazzar M. Yoza B.K. Chen X. Hu J. Hawkins G.A. McCall C.E. J. Biol. Chem. 2008; 283: 32198-32208Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 9El Gazzar M. Yoza B.K. Chen X. Garcia B.A. Young N.L. McCall C.E. Mol. Cell. Biol. 2009; 29: 1959-1971Crossref PubMed Scopus (120) Google Scholar). Information is limited on the nature of the molecular bridge between the transcription factors and epigenetic determinants. We discovered that de novo induction of NF-κB transcription factor RelB after TLR4 stimulation is necessary and sufficient for silencing transcription of TNFα and IL-1β in the SSI phenotype (8El Gazzar M. Yoza B.K. Chen X. Hu J. Hawkins G.A. McCall C.E. J. Biol. Chem. 2008; 283: 32198-32208Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 19Yoza B.K. Hu J.Y. Cousart S.L. Forrest L.M. McCall C.E. J. Immunol. 2006; 177: 4080-4085Crossref PubMed Scopus (96) Google Scholar). We also found that RelB can function in the same cell type as a dual transcription regulator in the SSI phenotype to deactivate transcription of acute proinflammatory genes while activating transcription of the NF-κB regulator IκBα (20Chen X. Yoza B.K. El Gazzar M. Hu J.Y. Cousart S.L. McCall C.E. Clin. Vaccine Immunol. 2009; 16: 104-110Crossref PubMed Scopus (39) Google Scholar). RelB also participates in constitutive silencing of inflammatory genes in fibroblasts by a process that supports regional methylation of CpG DNA (21Kruys V. Thompson P. Beutler B. J. Exp. Med. 1993; 177: 1383-1390Crossref PubMed Scopus (45) Google Scholar), and when normally silenced fibroblasts are rendered RelB−/−, they become responsive to LPS (22Xia Y. Chen S. Wang Y. Mackman N. Ku G. Lo D. Feng L. Mol. Cell. Biol. 1999; 19: 7688-7696Crossref PubMed Google Scholar). In this study, we examined how RelB couples to epigenetically silence expression of acute proinflammatory genes and found that RelB initiates facultative heterochromatin formation by interacting with the histone H3 lysine methyltransferase G9a, which then mediates heterochromatin formation. THP-1 cells obtained from American Type Culture Collection were maintained in RPMI 1640 medium (Invitrogen) supplemented with 10 units/ml penicillin G, 10 μg/ml streptomycin, 2 and at and in a that the SSI phenotype in THP-1 cells was previously McCall C.E. J. Exp. Med. PubMed Scopus Google Scholar). LPS is by an stimulation with LPS 1 for by with μg/ml LPS for This LPS through TLR4 receptor as in cells of LPS are used to the tolerant with as as and for at (3McCall C.E. Yoza B.K. Am. J. Respir. Crit. Care Med. 2007; 175: 763-767Crossref PubMed Scopus (71) Google Scholar). and LPS tolerant THP-1 cells were with RPMI in supplemented RPMI 1640 medium at 1 and with LPS 1 μg/ml for and cells were used for all G9a, and binding to the IL-1β promoter in LPS tolerant and were to the with the were by a into the medium for a of and at for 10 with The chromatin was by a on and for at this DNA of was into an that was with The other was with for p65 p50 RelB and for the control and G9a DNA was in 10 of The of was to a H. T. Chen J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). In cells were and as was with or and of protein with at 4 were by with 10 at for and in were then with DNA was in 10 of The DNA for was for the of the IL-1β promoter and and as we used The of DNA, of of and The was 2 at and 10 at by with at and 1 at the were to the DNA and are as to DNA from IL-1β was at various after LPS stimulation to the of was to in a 1 and The was 4 of and the were to and are as to from 2 of DNA, 1 of 2 and DNA was to the of The was 1 at for at and for a at for 10 The were on and were and protein was by The for protein are the same as we used B.K. Hu J.Y. Cousart S.L. Forrest L.M. McCall C.E. J. Immunol. 2006; 177: 4080-4085Crossref PubMed Scopus (96) Google Scholar). G9a, and were used to and protein of control and small interfering were by with of in of medium as previously B.K. Hu J.Y. Cousart S.L. Forrest L.M. McCall C.E. J. Immunol. 2006; 177: 4080-4085Crossref PubMed Scopus (96) Google Scholar). that of the gene to for by our that the expression of other inflammatory IκBα and is by the of into tolerant In data that RelB or G9a knockdown by the expression of the after cells were or with 1 μg/ml LPS to induce cells were and for with 1 μg/ml were and was and used to the IL-1β expression In binding of G9a and RelB was by were in and with the cell was in and and on for of cell 4 of were used for of of 4 of G9a RelB or and of protein were at 4 with were with 1 then with with of in of of were and with RelB or G9a by and used for and were in all with for of were at that the of the Rel homology domain and is for RelB J. R. Mol. Cell. Biol. PubMed Scopus Google Scholar). RelB RelB with was by DNA G9a and G9a were with the from human G9a by for The used for the G9a domain were and for G9a was DNA was into the and glutathione S-transferase The were by DNA and protein expression was confirmed by G9a were into from and the protein expression was by the of to a of 1 at for generate RelB with from from G. was to the The used for RelB were and pulldown was pulldown were and by and were are the of was at G9a and a complex with RelB at the IL-1β promoter transcription we the and that a of and to in among promoter as the and G9a and as we that a complex of the forms at the promoter of silenced cells DNA and were used as when we used G9a as the and RelB and as p65 at the promoter data that a cooperative complex of the transcription factor and histone modifiers at the silenced IL-1β they the functional of this they the binding of the are or RelB function as an initiating in facultative heterochromatin transcription we used RelB to the of RelB on the promoter binding of G9a and confirmed the expression of RelB protein after with RelB the of G9a and RelB of G9a, and at the IL-1β promoter with the control The small and the data are as independent were and the observed were The of the complex of transcription and chromatin mediators also with generation of the H3K9 dimethylation silencing and binding of p65 that the accumulation of G9a and at the IL-1β promoter is dependent on the of RelB and that chromatin modifiers may a in the histone from activating to silencing through histone H3K9 We previously reported that of type RelB transcription of IL-1β in THP-1 cells B.K. Hu J.Y. Cousart S.L. Forrest L.M. McCall C.E. J. Immunol. 2006; 177: 4080-4085Crossref PubMed Scopus (96) Google Scholar). This was as RelB is in whereas de novo induction of RelB in transcriptionally silenced THP-1 we induce of RelB and G9a in by of we a type or a a of the of RelB to RelB in THP-1 RelB protein expression in from cells with RelB type or RelB was of on of G9a or that of RelB but RelB binding of RelB and G9a to the IL-1β promoter. that of IL-1β after of type RelB but RelB These data that RelB initiates silencing by a process that requires the domain and that of the protein may provide the for silencing. RelB is necessary and sufficient for transcription silencing B.K. Hu J.Y. Cousart S.L. Forrest L.M. McCall C.E. J. Immunol. 2006; 177: 4080-4085Crossref PubMed Scopus (96) Google and the data in this a we the transcription silencing of RelB is by a to G9a. this we used to G9a a process that alter RelB or protein as by We then of G9a by as by with control G9a that of the promoter to LPS stimulation of IL-1β is in the G9a the of the G9a knockdown on of the promoter by RelB and in the of in G9a and of transcription we used The in that RelB to the IL-1β promoter at after G9a whereas and G9a are This that RelB silencing requires G9a-dependent modifications of In the we by and RelB and G9a binding to the promoter. The in RelB and G9a binding after that assembly at the IL-1β promoter is to RelB and G9a directly we used a of In of in silenced cells and of cells with the type RelB and G9a were used as and in the in In vitro of RelB and G9a were pulldown the and of G9a were to as and that RelB and G9a with or after of RelB and in silenced cells in the This supports that RelB and G9a in directly or that in vitro RelB directly with G9a in vitro and that this at the of G9a. and controls were The were data that RelB can initiate silencing by directly binding to G9a, which mediates formation of facultative as by the of (13Trojer P. Reinberg D. Mol. Cell. 2007; 28: 1-13Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar). This is the on a responsible for the between an NF-κB and the epigenetic events that chromatin to heterochromatin a to a lysine methyltransferase and heterochromatin protein These data provide novel insight into how RelB initiates silencing in the phenotype associated with severe systemic inflammation in humans, a disease with major morbidity and mortality. is dependent on the de novo induction of RelB by TLR4 The data a of RelB with the methyltransferase G9a, which through dimethylation of histone H3 at lysine 9 a binding for chromatin protein and supports a switch in the histone from to silenced transcription R. Mol. Cell. Biol. 2007; PubMed Scopus Google Scholar). We that whereas RelB is a of this silencing G9a is a in chromatin This is on that RelB the promoter in the of G9a which at a that transcription silencing is we also that that facultative heterochromatin chromatin to In RelB knockdown in of G9a and from the promoter as as of dimethylation of H3K9 and transcription silencing. of RelB in cells that RelB induces accumulation of G9a, and at the IL-1β promoter and silences transcription. in that the RelB is required for gene silencing. in vitro that the domain of G9a participates in this by directly interacting with RelB. data that transcription factors and interplay with DNA are to gene silencing by histone and DNA methylation are limited data how molecular for G9a or histones and DNA with transcription factors or The 1 transcriptional couples to G9a to silence gene transcription D. M. Mol. Cell. Biol. 2005; PubMed Scopus Google Scholar). protein also G9a to transcription of H. Sci. PubMed Scopus Google Scholar). 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Res. 2005; PubMed Scopus (45) Google Scholar). the required for binding transcription factors The G9a that to methylation on histones and the that are are in the the of RelB that after RelB to the promoter by the domain are G9a is a of epigenetic silencing. the G9a chromatin compaction process to histone H3K9 dimethylation and to methylation of lysine on linker histone H1 4 P. J. M. H. T. Reinberg D. J. Biol. Chem. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). methylation which facultative heterochromatin formation, and the process supports and at gene novel in this is that the accumulation of H1 and can reversed by the lysine an that to a to the of euchromatin and transcription. This of facultative heterochromatin formation dependent on histone H3K9 and linker histone H1 methylation modifications by G9a and may important in the SSI and THP-1 we reported that of H1 that is to as in and by RelB from the promoters of acute proinflammatory genes IL-1β and H3K9 and transcription silencing in cells Gazzar M. Yoza B.K. Chen X. Garcia B.A. Young N.L. McCall C.E. Mol. Cell. Biol. 2009; 29: 1959-1971Crossref PubMed Scopus (120) Google Scholar). This also to humans with as in the same we that linker histone H1 and in at the TNFα and IL-1β but the in blood leukocytes Gazzar M. Yoza B.K. Chen X. Garcia B.A. Young N.L. McCall C.E. Mol. Cell. Biol. 2009; 29: 1959-1971Crossref PubMed Scopus (120) Google Scholar). We also that RelB is and G9a and to the TNFα promoter of blood SSI human leukocytes (8El Gazzar M. Yoza B.K. Chen X. Hu J. Hawkins G.A. McCall C.E. J. Biol. Chem. 2008; 283: 32198-32208Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 19Yoza B.K. Hu J.Y. Cousart S.L. Forrest L.M. McCall C.E. J. Immunol. 2006; 177: 4080-4085Crossref PubMed Scopus (96) Google Scholar). We that RelB induction a and transcription regulator for activation and of distinct sets of genes in a and inflammatory as SSI. important is how the NF-κB control activation of proinflammatory and anti-inflammatory is that a of p65 may induce response genes including TNFα and IL-1β but also transcription factors that control reprogramming for expression of and This process may a of p65 activation by an signaling as α and require protein data this is a of the of the master control are NF-κB DNA across the our an for the RelB influence on the genetic that regulates This reprogramming may among inflammatory and inflammatory disease (3McCall C.E. Yoza B.K. Am. J. Respir. Crit. Care Med. 2007; 175: 763-767Crossref PubMed Scopus (71) Google Scholar), an important to the nature of the intracellular specificity that between transcription and activation by RelB is but in among the DNA promoter in to CpG for methylation may on the of our and the we provide in a model for epigenetic regulation of a set of acute proinflammatory genes SSI. SSI is often by processes that require NF-κB activation and binding of p65 with and to gene including of acute proinflammatory mediators as as reprogramming the early critical of the temporal of gene expression and the epigenetic reprogramming of SSI is expression of the NF-κB factor which as a of the silencing by with G9a. G9a as a in gene silencing through dimethylation of which a for recruitment of events that in chromatin compaction and are at in by G9a and CpG methylation and recruitment of linker histone H1 and at The of silenced facultative heterochromatin may for but can to euchromatin and in SSI this epigenetic plasticity may provide for for inflammatory We Hu and Cousart for
Chen et al. (Wed,) studied this question.