Epigenetics of Severe Systemic Inflammation

严重全身炎症的表观遗传学

• 批准号: 8389559
• 负责人: Charles Emory McCall
• 金额: $ 34.43万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8389559
• 关键词: Acute; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Binding Sites; Biochemical; Chromatin; Couples; Cytosine; DNA; DNA Sequence; Data; Disease; Epigenetic Process; Euchromatin; Feedback; Functional disorder; Genes; Genetic; Genetic Transcription; HMGB1 Protein; Heterochromatin; Histone H1; Histone H1(s); Histones; Human; Immunoblotting; Infectious Agent; Inflammation; Inflammation Mediators; Leukocytes; Link; Location; Maps; Mass Spectrum Analysis; Messenger RNA; Methylation; Methyltransferase; Morbidity - disease rate; NF-kappa B; Natural Immunity; Nucleosomes; Outcome; Peptides; Plasmids; Play; Positioning Attribute; Prevention; Process; Proteins; Public Health; Reporting; Research; Restriction Mapping; Role; SPT6 Protein; Sepsis; Signal Transduction; Small Interfering RNA; Specificity; Testing; Toll-like receptors; Transfection; Translational Research; Trauma; Work; adaptive immunity; antimicrobial; base; chromatin immunoprecipitation; chromatin remodeling; design; heterochromatin-specific nonhistone chromosomal protein HP-1; histone modification; improved; mortality; novel; novel therapeutic intervention; p65; peripheral blood; promoter; public health relevance; response; toll-like receptor 4

DESCRIPTION (provided by applicant): Severe systemic inflammation (SSI) with multiorgan dysfunction from sepsis or non infectious agents is a disease with major mortality and morbidity. SSI is associated with gene-specific reprogramming of innate immunity leukocyte responses to Toll-like receptor (TLR)-4dependent signaling, which epigenetically represses transcription of a set of acute proinflammatory genes, while activating other sets of genes that generate anti- inflammatory mediators and anti-microbial peptides. This gene reprogramming is important in at least two ways. Its presence indicates repressed innate and adaptive immunity and its reversal correlates with improved outcomes in SSI in humans and animals. We have reported that the epigenetic silencing signature requires Toll-like receptor 4 (TLR4) induction of NF-kappa B factor RelB that disrupts p65 promoter binding, directs histone H3K9 di-methylation by G9a to provide a binding site of heterochromatin protein 1 (HP1), which then links to DNA CpG methylation responses and chromatin structural proteins. This RelB-dependent process alters the state of responsive euchromatin to produce silenced facultative heterochromatin. The general objective of our research is to define mechanisms that shift chromatin between the euchromatin and facultative heterochromatin states. This proposal tests the hypothesis that G9a and RelB provide a bond for both assembling and disassembling facultative heterochromatin during SSI by its ability to directly bind G9a, which couples to histone and DNA modifiers and structural chromatin proteins like linker histone H1 and high mobility group box 1 (HMGB1) proteins. Aim 1 will test for direct interaction and feedback between G9a and RelB to initiate and reverse gene-specific change from active euchromatin to facultative heterochromatin at the proximal promoters of acute proinflammatory genes TNFa and IL-1b. Aim 2 will test whether the linker histone H1, in concert with HMGB1, sustains heterochromatin assembly and transcription silencing by re-positioning nucleosomes and maintaining RelB and G9a binding at promoter sequences of TNFa and IL-1b. Aim 3 will use human peripheral blood leukocytes to extend the gene-specific reprogramming paradigm to human SSI. Our experimental approaches will employ genetic and biochemical analyses.]

描述（由申请人提供）：严重的全身性炎症（SSI），具有败血症或非传染性药物的多器官功能障碍是一种具有重大死亡率和发病率的疾病。 SSI与先天性免疫白细胞对TOLL样受体（TLR）-4依赖性信号的反应的基因特异性重编程有关，该信号表观遗传抑制了一组急性促炎基因的转录，同时激活其他产生抗炎性腺苷酸的基因组，并产生抗炎性膜中的基因和抗抗抗菌抗体。 该基因重编程至少在两种方面很重要。 它的存在表明抑制了先天性和适应性免疫，并且其逆转与人类和动物的SSI结果的改善相关。 We have reported that the epigenetic silencing signature requires Toll-like receptor 4 (TLR4) induction of NF-kappa B factor RelB that disrupts p65 promoter binding, directs histone H3K9 di-methylation by G9a to provide a binding site of heterochromatin protein 1 (HP1), which then links to DNA CpG methylation responses and chromatin structural蛋白质。 这种依赖性的过程改变了反应式圣染色质的状态，以产生沉默的兼性异染色质。 我们研究的总体目标是定义在斑塑素和兼性异染色质状态之间转移染色质的机制。 该提案检验了以下假设：SSI期间G9A和RERB通过其直接结合G9A的能力为组装和分解辅助异染色质提供了键，它们将其与组蛋白和DNA修饰剂和结构染色质蛋白（如连接器H1）和高移动性H1和High Mobilitial oftoility H1（HIM Mobilitial ofter Box 1（HMGB1）相结合。 AIM 1将测试G9A和RELB之间的直接相互作用和反馈，以在急性促炎基因TNFA和IL-1B的近端启动子上启动和反向基因特异性变化。 AIM 2将通过重新放置核小体并将RELB和G9A结合在TNFA和IL-1B的启动子序列上维持RELB和G9A结合来测试与HMGB1的接头H1是否可以维持异染色质组装和转录沉默。 AIM 3将使用人类外周血白细胞将基因特异性重编程范式扩展到人类SSI。 我们的实验方法将采用遗传和生化分析。]