The impact of microbial metabolites on the chromatin landscape and gene regulation

微生物代谢物对染色质景观和基因调控的影响

• 批准号: 10001976
• 负责人: Leah Ashley Gates
• 金额: $ 7.01万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2021-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001976
• 关键词: Ablation; Acetylation; Acylation; Address; Antibiotic Therapy; Biological Assay; Biological Models; Biology; Cecum; Cell Fractionation; Cell Nucleus; Cell physiology; Cells; Chemicals; Chromatin; Data; Dependence; Deposition; Dietary Fiber; Disease; Environment; Enzymes; Exposure to; Fermentation; Fostering; Gastrointestinal tract structure; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Transcription; Genomics; Germ-Free; Health; Histone Acetylation; Histones; Human; Immunofluorescence Immunologic; Intestines; Large Intestine; Lysine; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Metabolic; Microbe; Modeling; Modification; Molecular; Mus; Nucleosomes; Outcome; Pathology; Physiological; Physiological Adaptation; Physiology; Play; Post-Translational Protein Processing; Proteins; Reaction; Reader; Regulation; Reporting; Role; Small Intestines; Stains; Stimulus; System; Testing; Tissues; Transcriptional Regulation; Volatile Fatty Acids; acyl group; base; chromatin immunoprecipitation; defined contribution; epigenome; epigenomics; gut microbiome; insight; knock-down; metabolome; metabolomics; microbial; microbiome; microbiota; microbiota metabolites; novel; programs; recruit; response; tissue culture; transcriptome sequencing

Project Summary Many aspects of human physiology and disease are closely tied to the state of the gut microbiome, yet determining mechanisms by which the microbiome exerts effects at the cellular level is still an open question. Microbes break down dietary fiber, which results in the generation of short chain fatty acids (SCFAs) as metabolic byproducts. These fermentation reactions create an environment in the gastrointestinal tract with high concentrations of SCFAs, which can then act on neighboring host cells. Recently, SCFAs have been detected as chemical modifications on histone proteins, called histone acyl marks, suggesting that a portion of these metabolites enter the nucleus for deposition onto chromatin. While certain histone acyl marks have been reported to positively regulate transcription, including the well-studied histone acetylation, the mechanistic functional role of newer acyl marks such as histone butyrylation are largely unknown. In addition, how SCFAs are regulated in the cell to enter the nucleus and act on chromatin is undetermined. In the mouse intestine, particular acyl modifications on histones are positively correlated with the presence of microbes. In addition, antibiotic treatment reduces levels of histone acyl marks, suggesting select histone acyl marks are dependent on the microbiota. This dependency of histone acyl marks on the microbiota occurs in a tissue-specific manner, with the highest differences observed in the cecum, where the small and large intestines intersect. Now we aim to determine the function of specific microbiota-dependent chromatin acyl marks on gene expression using the mouse gut as a model system. We hypothesize that SCFAs are written onto chromatin as histone acylations in a regulated manner, which mediate key transcriptional programs in response to the microbial environment. To address this hypothesis, the mechanistic function of select histone acyl marks in gene regulation will be investigated, through the use of the mouse gut as a model to study these histone marks. In addition, microbiota-dependent chromatin acyl marks and metabolites will be defined in a comprehensive manner. Lastly, the regulation of histone acyl marks by metabolic enzymes will also be determined. Together, completion of these aims will expand our understanding of the physiological roles of novel histone marks, and will also provide mechanistic insight into how the microbiome impacts the chromatin landscape. Furthermore, this proposal will elucidate the functions of histone acyl marks through chromatin reader protein recruitment and downstream regulation of transcription.

项目概要 人类生理学和疾病的许多方面都与肠道微生物组的状态密切相关，然而 确定微生物组在细胞水平发挥作用的机制仍然是一个悬而未决的问题。 微生物分解膳食纤维，从而产生短链脂肪酸 (SCFA) 代谢副产物。这些发酵反应在胃肠道中创造了一个环境 高浓度的 SCFA，然后可以作用于邻近的宿主细胞。最近，SCFA 检测到组蛋白上的化学修饰，称为组蛋白酰基标记，这表明 这些代谢物进入细胞核沉积在染色质上。虽然某些组蛋白酰基标记已被 据报道可以积极调节转录，包括经过充分研究的组蛋白乙酰化、机制 较新的酰基标记（例如组蛋白丁酰化）的功能作用在很大程度上尚不清楚。此外，SCFA 如何 在细胞中受调节进入细胞核并作用于染色质尚未确定。在小鼠肠道中， 组蛋白上的特定酰基修饰与微生物的存在呈正相关。此外， 抗生素治疗降低了组蛋白酰基标记的水平，表明选择的组蛋白酰基标记是依赖的 关于微生物群。组蛋白酰基标记对微生物群的这种依赖性以组织特异性方式发生， 在小肠和大肠相交的盲肠中观察到的差异最大。现在我们的目标是 使用以下方法确定特定微生物群依赖性染色质酰基标记对基因表达的功能 小鼠肠道作为模型系统。我们假设 SCFA 以组蛋白酰化形式写入染色质 一种调节方式，调节关键转录程序以响应微生物环境。到 为了解决这个假设，选择组蛋白酰基标记在基因调控中的机制功能将是 通过使用小鼠肠道作为模型来研究这些组蛋白标记进行了研究。此外， 微生物依赖的染色质酰基标记和代谢物将以全面的方式进行定义。 最后，还将确定代谢酶对组蛋白酰基标记的调节。一起， 完成这些目标将扩大我们对新组蛋白标记的生理作用的理解，并且 还将提供微生物组如何影响染色质景观的机制见解。此外， 该提案将通过染色质读取蛋白招募来阐明组蛋白酰基标记的功能 和下游转录调控。