Epigenetics of the human gut microbiome

人类肠道微生物组的表观遗传学

• 批准号: 10626761
• 负责人: Eric John Alm
• 金额: $ 36.81万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626761
• 关键词: 7-deazaguanine; Address; Adenine; Affect; Bacteria; Bacterial DNA; Bacterial Genome; Bacteriophages; Behavior; Cell Cycle; Chemicals; Chemistry; Chromatography; Clinical; Collaborations; Colon Carcinoma; Consumption; Coupled; DNA; DNA Methylation; DNA Modification Process; DNA Restriction-Modification Enzymes; Development; Disease; Epigenetic Process; Equilibrium; Etiology; Flare; Gene Expression; Genes; Genetic Engineering; Genome; Genomic Instability; Genomics; Goals; Health; Heritability; Human; Human Microbiome; Immune system; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory Bowel Diseases; Inherited; Libraries; Link; Maps; Mass Spectrum Analysis; Metagenomics; Methyltransferase; Microbe; Modification; Mus; Mycobacterium abscessus; Oxidation-Reduction; Oxidative Stress; Oxygen; Patients; Phenotype; Play; Population; Predisposition; Proteins; Pseudomonas aeruginosa infection; Research; Resistance; Role; Sampling; Sulfur; System; Testing; Vertebral column; Virulence; Wound Infection; analytical tool; bacterial fitness; computerized tools; epigenome; gene function; genomic tools; gut bacteria; gut inflammation; gut microbes; gut microbiome; gut microbiota; human disease; human microbiota; informatics tool; innovation; innovative technologies; microbial; microbiome; microbiome research; neutrophil; new technology; next generation sequencing; novel; oxidation; pathogen; pathogenic bacteria; phosphorothioate; programs; tool; virtual

Project Summary The proposed studies address the role of bacterial epigenetics in the human gut microbiome and their mechanistic links to health and disease. Virtually all microbes possess DNA modifications – the epigenome -- inherited marks that regulate gene expression and function as immune systems, most commonly in restriction- modification (RM). While well-characterized DNA methylation-based RM systems have been known since the 1970s, there are now >30 DNA modifications defined in bacteria and bacteriophage, including our recent discovery of phosphorothioate (PT) and 7-deazaguanine modifications. DNA modifications also regulate gene expression, such as the DNA adenine methyltransferase, DAM, and cell cycle-regulated methylase, CcrM, which control heritable gene expression affecting virulence and bacteriophage resistance, as well as non- heritable gene expression. While these examples of bacterial epigenetics have links to human disease, we know little about how DNA modifications determine or affect microbial populations in the gut, how they affect the behavior or survival of individual microbial species, or if there is a relationship between specific microbiome epigenetics and human health and disease. Here we use innovative analytics, informatics, and genomics tools to explore these questions, with an initial focus on a bacterial DNA modification found in ~15% of human gut microbes: PT modifications, in which a redox-active S replaces a non-bonding oxygen in the DNA backbone. The proposed studies are driven by the widespread distribution of PTs in bacterial pathogens and commensals, the susceptibility of PTs to oxidation by chemical mediators of inflammation, and the known effects of inflammation on gut microbiota, all of which suggest that inflammation could alter the balance of PT-containing gut microbes. However, we know virtually nothing about microbiome epigenetics, much less which gut bacteria possess redox-sensitive PTs and other epigenetic marks. We now propose to define the landscape of PT-containing bacteria in the healthy human gut, elucidate the role of PTs in microbiome changes during gut inflammation, and discover new epigenetic marks in the gut microbiome. We start by quantifying PTs and identifying PT-containing bacteria in fecal DNA samples from healthy donors to the Broad Microbiome Library and in ~7000 strains cultured from these samples (dnd genes found in 15%). We then test the idea that redox-sensitive PTs affect bacterial fitness in the inflamed gut, quantifying PT levels and PT-containing bacteria in 20-30 fecal samples from inflammatory bowel disease (IBD) patients. Finally, we will identify new DNA modifications in gut microbes, using novel technologies to discover DNA marks in banked fecal samples from BML donors and strains, and then link them to unique microbiome phenotypes and associations with human disease. The significance of this project lies in the potential role for PT-containing microbes in human health and disease, the potential clinical impact of PT- containing bacteria on IBD, and the development of new tools to discover new microbiome epigenetic systems.

项目概要 拟议的研究探讨了细菌表观遗传学在人类肠道微生物组中的作用及其 几乎所有微生物都具有 DNA 修饰（表观基因组）。 调节基因表达和免疫系统功能的遗传标记，最常见的是限制性- 修饰（RM）。 20 世纪 70 年代，现在细菌和噬菌体中定义了超过 30 个 DNA 修饰，包括我们最近的 硫代磷酸酯 (PT) 和 7-脱氮鸟嘌呤修饰的发现也调节基因。 表达，例如 DNA 腺嘌呤甲基转移酶 DAM 和细胞周期调节甲基化酶 CcrM， 它控制影响毒力和噬菌体抗性的遗传基因表达，以及非 虽然这些细菌表观遗传学的例子与人类疾病有关，但我们 对于 DNA 修饰如何决定或影响肠道微生物种群、它们如何 影响单个微生物物种的行为或生存，或者之间是否存在关系 特定的微生物组表观遗传学和人类健康和疾病。 信息学和基因组学工具来探索这些问题，最初的重点是细菌 DNA 在大约 15% 的人类肠道微生物中发现了修饰：PT 修饰，其中氧化还原活性 S 取代了 DNA骨架中非键合氧的广泛分布推动了这项研究。 细菌病原体和共生体中的PT，PT对化学介质氧化的敏感性 炎症以及炎症对肠道微生物群的已知影响，所有这些都表明炎症 可能会改变含有 PT 的肠道微生物的平衡然而，我们对微生物组几乎一无所知。 表观遗传学，更不用说哪些肠道细菌拥有氧化还原敏感的 PT 和其他表观遗传标记。 提议定义健康人类肠道中含 PT 的细菌的状况，阐明其作用 肠道炎症期间微生物组中 PT 的变化，并发现肠道中新的表观遗传标记 我们首先对粪便 DNA 样本中的 PT 进行定量并鉴定含有 PT 的细菌。 广泛微生物组库的健康供体以及从这些样本中培养的约 7000 株菌株（dnd 基因） 发现于 15%），然后我们测试了氧化还原敏感 PT 影响发炎肠道细菌适应性的观点， 量化 20-30 个炎症性肠病粪便样本中的 PT 水平和含 PT 的细菌 最后，我们将利用新技术识别肠道微生物中新的 DNA 修饰。 在来自 BML 供体和菌株的储存粪便样本中发现 DNA 标记，然后将它们与独特的 微生物组表型及其与人类疾病的关联该项目的意义在于 含 PT 的微生物在人类健康和疾病中的潜在作用，PT-的潜在临床影响 含有 IBD 细菌，以及开发新工具来发现新的微生物组表观遗传系统。