Epigenetics of Severe Systemic Inflammation

严重全身炎症的表观遗传学

• 批准号: 8246552
• 负责人: Charles Emory McCall
• 金额: $ 8.94万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246552
• 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.] PUBLIC HEALTH RELEVANCE: Severe systemic inflammation (SSI) from sepsis or trauma has substantial public health impact through its high mortality and sustained morbidity. This translational research should define novel mechanisms responsible for the epigenetic basis for gene reprogramming in inflammation. From these results, novel therapeutic interventions or preventions may be designed to improve the poor outcomes associated with SSI.

描述（由申请方提供）：脓毒症或非感染性病原体引起的伴有多器官功能障碍的重度全身性炎症（SSI）是一种死亡率和发病率较高的疾病。 SSI与先天免疫白细胞对Toll样受体（TLR）-4依赖性信号的应答的基因特异性重编程相关，其表观遗传学上抑制一组急性促炎基因的转录，同时激活产生抗炎介质和抗微生物肽的其他基因组。 这种基因重编程至少在两个方面很重要。 它的存在表明先天和适应性免疫受到抑制，其逆转与人类和动物SSI的改善结果相关。 我们已经报道了表观遗传沉默签名需要Toll样受体4（TLR 4）诱导NF-κ B因子RelB，其破坏p65启动子结合，指导组蛋白H3 K9通过G9 a去甲基化以提供异染色质蛋白1（HP 1）的结合位点，然后连接到DNA CpG甲基化反应和染色质结构蛋白。 这种依赖RelB的过程改变了反应性常染色质的状态，产生沉默的兼性异染色质。 我们研究的总目标是确定常染色质和兼性异染色质状态之间的染色质转换机制。 该提议测试了G9 a和RelB通过其直接结合G9 a的能力为SSI期间的兼性异染色质的组装和分解提供键的假设，G9 a与组蛋白和DNA修饰剂以及结构染色质蛋白如接头组蛋白H1和高迁移率族蛋白1（HMGB 1）蛋白偶联。 目的1将测试G9 a和RelB之间的直接相互作用和反馈，以在急性促炎基因TNF α和IL-1b的近端启动子处启动和逆转从活性常染色质到兼性异染色质的基因特异性变化。 目的2将测试连接体组蛋白H1是否与HMGB 1一致，通过重新定位核小体并维持RelB和G9 a结合在TNF α和IL-1b的启动子序列来维持异染色质组装和转录沉默。 目的3将使用人外周血白细胞将基因特异性重编程范例扩展到人SSI。 我们的实验方法将采用遗传和生物化学分析。 公共卫生关系：脓毒症或创伤引起的严重全身性炎症（SSI）通过其高死亡率和持续发病率对公共卫生产生重大影响。 这种转化研究应该定义负责炎症中基因重编程的表观遗传基础的新机制。 根据这些结果，可以设计新的治疗干预或预防措施来改善与SSI相关的不良结局。