Cooption of the DNA Damage Response For Epigenetic Regulation of Inflammation

炎症表观遗传调控的 DNA 损伤反应的共同选择

• 批准号: 10533304
• 负责人: Steven Zvi Josefowicz
• 金额: $ 42.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533304
• 关键词: Amino Acids; Amplifiers; Autoimmunity; Biochemical; Biology; CHEK1 gene; Cells; Chromatin; Complex; Cues; DNA; DNA Damage; DNA Polymerase II; DNA Topoisomerases; Dedications; Dependence; Disease; Environmental Risk Factor; Epigenetic Process; Event; Gene Expression; Genes; Genetic Transcription; Genome; Goals; Histone Code; Histone H3; Histone H3.3; Histones; Human; Immune; Immunity; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Link; Macrophage; Mediating; Memory; Molecular; Mutation; Oncogenic; Organism; Paper; Pathway interactions; Phosphorylation; Polymerase; Positioning Attribute; Post-Translational Protein Processing; Proteins; Role; Serine; Signal Pathway; Signal Transduction; Site; Specificity; Speed; Tail; Therapeutic; Time; Tissues; Topoisomerase; Training; Transcription Coactivator; Variant; Yeasts; activating transcription factor 1; cell type; epigenetic regulation; epigenomics; experimental study; extracellular; gene induction; in vivo; insight; meter; mutant mouse model; novel; pathogen; protein H(3); recruit; response; therapeutic target; transcription factor; transmission process; tumor; upstream kinase

Project Summary Complex organisms are able to rapidly induce select genes among thousands in response to diverse environmental cues. This occurs in the context of large genomes condensed with histone proteins into chromatin. The macrophage response to pathogen sensing, for example, rapidly engages highly conserved signaling pathways and transcription factors (TFs) for coordination of inflammatory gene induction. Enriched integration of histone H3.3, the ancestral histone H3 variant, is a feature of inflammatory genes and, in general, dynamically regulated chromatin and transcription. The amino-terminal H3.3 `tail' differs from the other H3 proteins by a single amino acid, a serine at position 31. However, little is known of how (or which) features of H3.3, conserved from yeast to human, might enable rapid and high-level transcription. We have recently discovered a potent function for H3.3-specific histone phosphorylation (H3.3S31ph) in inflammatory gene transcription and surprising evidence that non-canonical activity of the DNA-damage response (DDR) pathway mediates this histone phosphorylation. Thus, we hypothesize that the DDR pathway is coopted for epigenetic regulation of inflammatory genes. In Aim 1 we will identify the factors and sequence of events that link DDR factors and H3.3S31ph to rapid inflammatory gene transcription and reveal the function of cross-talk between DDR and chromatin (H3.3S31ph) by employing novel histone mutant mouse models. Specifically, our experiments will enable us to distinguish between several candidate “paths” to H3.3S31ph and amplification of transcription, including Topoisomerase dependency, and DNA break-dependent and -independent pathways. In Aim 2 we will identify how DDR-mediated H3.3S31ph uniquely regulates Pol II dynamics at select inflammatory genes to amplify their transcription. More generally, these studies will identify dedicated mechanisms that enable inflammatory gene induction with important implications for understanding inflammation and for informing more selective therapeutic strategies for diverse inflammatory diseases.

项目摘要 复杂的生物体能够从数千个基因中快速诱导出精选基因，以响应不同的 环境线索。这发生在大基因组与组蛋白浓缩成 染色质。例如，巨噬细胞对病原体感应的反应迅速地与高度保守的 协调炎症基因诱导的信号通路和转录因子。丰富 整合组蛋白H3.3，祖先的组蛋白H3变体，是炎症基因的一个特征，通常， 动态调节染色质和转录。氨基末端H3.3‘Tail’与其他H3不同 蛋白质由单一氨基酸组成，第31位是丝氨酸。然而，对如何(或哪些)功能知之甚少 H3.3在酵母和人类之间保守，可能使快速和高水平转录成为可能。我们最近做了 在炎症基因中发现H3.3特异性组蛋白磷酸化(H3.3S31ph)的有效功能 转录和令人惊讶的证据表明DNA损伤反应(DDR)途径的非规范活性 介导组蛋白的磷酸化。因此，我们假设DDR途径被用于表观遗传 炎症基因的调控。在目标1中，我们将确定将复员方案联系起来的因素和事件顺序 因子和H3.3S31ph对快速炎症基因转录和揭示串扰功能之间的影响 DDR和染色质(H3.3S31ph)通过使用新的组蛋白突变小鼠模型。具体地说，我们的 实验将使我们能够区分几条通往H3.3S31ph的候选“路径”和放大 转录，包括拓扑异构酶依赖，以及DNA断裂依赖和非依赖途径。 在目标2中，我们将确定DDR介导的H3.3S31ph如何在SELECT中独特地调节POL II动态 炎性基因来放大它们的转录。更广泛地说，这些研究将确定专门的 致炎基因诱导的机制及其对理解的重要意义 为各种炎症性疾病提供更多有选择性的治疗策略。