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: 10062828
• 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/10062828
• 关键词: Amino Acids; Amplifiers; Autoimmunity; Biochemical; Biology; CHEK1 gene; Cells; Chromatin; Complex; Cues; DNA; DNA Damage; DNA Polymerase II; DNA Topoisomerases; Dependence; Disease; Environmental Risk Factor; Epigenetic Process; Event; Gene Expression; Genes; Genetic Transcription; Genome; Goals; Histone Code; Histone H3; Histones; Human; Immune; Immunity; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Link; 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; cell type; crosslink; epigenetic regulation; epigenomics; experimental study; extracellular; gene induction; in vivo; insight; macrophage; meter; mutant mouse model; novel; pathogen; protein H(3); recruit; response; therapeutic target; transcription factor; 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 复杂的生物体能够在数千个基因中快速诱导选择基因，以响应不同的环境条件。 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 信号传导途径和转录因子（TF）协调炎症基因诱导。丰富 组蛋白H3.3（祖先组蛋白H3变体）的整合是炎性基因的特征，一般来说， 动态调节染色质和转录。氨基末端H3.3“尾”不同于其他H3 蛋白质由一个氨基酸组成，在31位有一个丝氨酸。然而，很少有人知道如何（或哪些）的特点， H3.3基因在酵母和人类中是保守的，可能使其能够快速和高水平转录。我们最近 发现炎症基因H3.3特异性组蛋白磷酸化（H3.3S31ph）的潜在功能 转录和令人惊讶的证据表明，DNA损伤反应（DDR）途径的非经典活性 介导组蛋白磷酸化。因此，我们假设DDR途径被选择用于表观遗传， 调节炎症基因。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对炎症基因快速转录的影响，并揭示了它们之间的相互作用。 DDR和染色质（H3.3S31ph）。具体来说，我们 实验将使我们能够区分H3.3S31ph的几个候选“路径”和H3.3S31ph的扩增。 转录，包括拓扑异构酶依赖性和DNA断裂依赖性和非依赖性途径。 在目标2中，我们将确定DDR介导的H3.3S31ph如何独特地调节Pol II动力学， 炎症基因来放大它们的转录。更一般地说，这些研究将确定专门的 炎症基因诱导的机制对理解 炎症和为不同的炎性疾病提供更有选择性的治疗策略。