Chromatin-Specific Remodeling by HMGB1 and Linker Histone H1 Silences Proinflammatory Genes during Endotoxin Tolerance
Chromatin-Specific Remodeling by HMGB1 and Linker Histone H1 Silences Proinflammatory Genes during Endotoxin Tolerance
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DOI：
10.1128/mcb.01862-08
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发表时间：
2009-04-01
影响因子：
5.3
通讯作者：
McCall, Charles E.
中科院分区：
文献类型：
--
作者：
El Gazzar, Mohamed;Yoza, Barbara K.;McCall, Charles E.
肿瘤坏死因子α (tnf - α)和白细胞介素1 β (IL-1 β)转录的表观遗传沉默发生在动物和人类的血液白细胞中，在严重全身性炎症（SSI）开始后。我们之前报道过，表观遗传特征需要诱导NF-kappa B因子RelB，该因子指导组蛋白H3K9二甲基化，破坏转录激活因子NF-kappa B p65的组装，并诱导从常染色质到异染色质的持续切换。在这里，我们报告了新的发现，细胞内高迁移率组框1蛋白（HMGB1）和核小体连接蛋白H1蛋白是内毒素介导的THP-1人促单核细胞中tnf - α沉默的必要成分。HMGB1在转录沉默期间结合tnf - α启动子并促进抑制因子RelB的组装。小干扰RNA耗尽HMGB1导致RelB与启动子分离，部分恢复tnf - α转录。组蛋白H1通常将HMGB1从核小体DNA中置换，也与HMGB1一起结合到沉默的tnf - α启动子的异染色质上。HMGB1和H1的联合敲低恢复了转录活性NF-kappa B p65的结合，并重建了tnf - α mRNA水平。染色质再免疫沉淀实验表明，HMGB1和H1可能独立募集到tnf - α序列，它们的结合与组蛋白H3K9二甲基化相关，因为组蛋白甲基化抑制了HMGB1和H1的结合。此外，在内毒素沉默过程中，HMGB1-和h1介导的染色质修饰是基因特异性的，因为它们也结合并抑制急性促炎IL-1 β，而未观察到抗炎I κ B α的结合或抑制。最后，我们发现H1和HMGB1与从SSI患者获得的人白细胞中的tnf - α启动子结合。我们得出结论，促炎HMGB1和结构核小体连接体H1偶对是表观遗传复合物的一个组成部分，该复合物在SSI表型中异染色质组装过程中沉默急性促炎tnf - α。
Epigenetic silencing of tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) 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-1 beta, 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.