Understanding the role of histone3 lysine4 trimethylation in neontal innate immune development under normal and inflammatory conditions

了解组蛋白 3 赖氨酸 4 三甲基化在正常和炎症条件下新生儿先天免疫发育中的作用

• 批准号: 10552063
• 负责人: Jennifer Bermick
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-07 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552063
• 关键词: ATAC-seq; Adaptive Immune System; Adult; Advanced Development; Affect; Asthma; Birth; Bone Marrow; Cells; Cessation of life; ChIP-seq; Chemotaxis; Child; Chorion; Chromatin; Chromatin Structure; Chronic; Defect; Deposition; Development; Disease; Environment; Exhibits; Experimental Models; Exposure to; Gastrointestinal tract structure; Gene Expression; Gene Expression Profile; Gene Silencing; Genes; Genetic Code; Genetic Transcription; Germ-Free; Health; Histones; Homeostasis; Human; IFNAR1 gene; Immune; Immune System Diseases; Immune response; Immune system; Immunologics; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interferons; Intestines; Lysine; MLL gene; Macrophage; Mediating; Methylation; Methyltransferase; Microbe; Mixed-Lineage Leukemia; Modeling; Mus; Myelogenous; Neonatal; Outcome; Pattern; Perinatal; Phenotype; Placenta; Predisposition; Premature Birth; Process; Role; Signal Transduction; Site; Skin colonization; Sterility; Systems Development; Techniques; Time; amnion; cytokine; early childhood; early life exposure; experimental study; extreme prematurity; fetal; fighting; global health; high risk; histone modification; immunoregulation; improved; in utero; infancy; intraamniotic infection; intrauterine environment; microbial; microbial colonization; monocyte; mouse model; neonatal death; neonatal immune system; neonatal infection; neonatal period; neonatal sepsis; neonate; offspring; pathogen; postnatal; preterm newborn; prevent; promoter; response; success; therapeutic target; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Neonates have dampened expression of pro-inflammatory cytokines and difficulty clearing pathogens, making them uniquely susceptible to infections. This is a worldwide health problem, with neonatal infections contributing to nearly one million deaths each year. The factors controlling neonatal specific immune responses and how and when they transition to more mature responses are poorly understood. Neonates rely heavily on innate immune responses to fight infections due to major defects in their adaptive immune system. Monocytes and macrophages are central to innate immune responses by sensing pathogens and initiating an inflammatory cascade that directs their clearance. Although both neonatal and adult monocytes/macrophages contain the same genetic code, they exhibit dramatic differences in pathogen-induced gene expression. Post- translational histone modifications can regulate gene transcription by influencing chromatin structure and accessibility, and likely play a role in this. Monocytes/macrophages demonstrate a developmental stage- specific increase in the H3K4 methyltransferase MLL1 with an associated gain in the activating histone modification histone 3 lysine 4 trimethylation (H3K4me3) at promoter sites of immunologically important genes as development progresses from extremely preterm neonate to adult. This gain allows for increasingly robust inflammatory responses as development advances. Microbial colonization of the skin and gastrointestinal tract occurs after birth and is associated with type 1 interferon expression, which is believed to guide immune system maturation and prevent detrimental pathogen responses. Chorioamnionitis is an inflammatory process affecting neonates around the time of birth, which negatively impacts immune system development and predisposes exposed neonates to long-term immune-related complications. The central hypothesis of this proposal is that neonatal monocytes/macrophages are largely un-patterned with H3K4me3 due to lack of in utero microbial exposure, and that postnatal microbial exposure stimulates low grade type 1 IFN expression which drives MLL1 expression and directs macrophage H3K4me3 deposition in a developmental stage-specific manner. Chorioamnionitis exposure stimulates a developmentally inappropriate level of type 1 interferon expression, which results in dysregulated MLL1 expression and global remodeling of the neonatal monocyte/macrophage landscape with subsequent dysfunctional monocyte/macrophage responses. This hypothesis will be investigated via the following specific aims: 1) Characterize normal human monocyte H3K4me3 patterning during infancy and early childhood and determine how developmental stage-specific H3K4me3 monocyte patterning impacts chromatin accessibility and gene expression, 2) Determine the requirement and sufficiency of type 1 interferons in MLL1-driven H3K4me3 placement in murine macrophage development and function, and 3) Determine the roles of type 1 interferons and MLL1 in chorioamnionitis-induced murine macrophage H3K4me3 remodeling and subsequent function.

项目概要/摘要 新生儿促炎细胞因子的表达受到抑制，并且难以清除病原体，这使得 他们特别容易受到感染。这是一个全球性的健康问题，其中包括新生儿感染 每年造成近一百万人死亡。新生儿特异性免疫的控制因素 人们对这些反应以及如何以及何时过渡到更成熟的反应知之甚少。新生儿靠 由于适应性免疫系统的重大缺陷，严重依赖先天免疫反应来对抗感染。 单核细胞和巨噬细胞通过感知病原体并启动免疫反应，是先天免疫反应的核心。 指导其清除的炎症级联反应。尽管新生儿和成人单核细胞/巨噬细胞 含有相同的遗传密码，它们在病原体诱导的基因表达方面表现出巨大的差异。邮政- 翻译组蛋白修饰可以通过影响染色质结构来调节基因转录 可访问性，并可能在其中发挥作用。单核细胞/巨噬细胞表现出一个发育阶段- H3K4 甲基转移酶 MLL1 的特异性增加与激活组蛋白的相关增益 免疫学重要基因启动子位点的组蛋白 3 赖氨酸 4 三甲基化 (H3K4me3) 修饰 从极早产新生儿到成人的发育过程。这种增益允许越来越鲁棒 随着发育的进展而产生炎症反应。皮肤和胃肠道的微生物定植 发生在出生后，与 1 型干扰素表达相关，据信干扰素可引导免疫 系统成熟并防止有害的病原体反应。绒毛膜羊膜炎是一种炎症过程 影响新生儿出生时的情况，对免疫系统发育产生负面影响 暴露的新生儿容易出现长期免疫相关并发症。这个假设的中心假设 建议认为，由于缺乏 H3K4me3，新生儿单核细胞/巨噬细胞在很大程度上没有 H3K4me3 模式。 子宫内微生物暴露，以及产后微生物暴露会刺激低级别 1 型干扰素 驱动 MLL1 表达并指导巨噬细胞 H3K4me3 沉积的表达 发展阶段特定的方式。接触绒毛膜羊膜炎会刺激发育 1 型干扰素表达水平不适当，导致 MLL1 表达失调 新生儿单核细胞/巨噬细胞景观的整体重塑以及随后的功能障碍 单核细胞/巨噬细胞反应。该假设将通过以下具体目标进行研究：1) 描述婴儿期和幼儿期正常人单核细胞 H3K4me3 模式的特征并确定 发育阶段特异性 H3K4me3 单核细胞模式如何影响染色质可及性和基因 表达，2)确定MLL1驱动的H3K4me3中1型干扰素的需求和充足性 在小鼠巨噬细胞发育和功能中的定位，以及 3) 确定 1 型干扰素的作用 和 MLL1 在绒毛膜羊膜炎诱导的小鼠巨噬细胞 H3K4me3 重塑和后续功能中的作用。