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.

项目摘要 人类生理和疾病的许多方面与肠道微生物组的状态紧密相关，但 确定微生物组在细胞水平上发挥作用的机制仍然是一个开放的问题。 微生物分解饮食纤维，这导致短链脂肪酸（SCFA）的产生 代谢副产品。这些发酵反应在胃肠道中创造了一个环境 高浓度的SCFA可以作用于相邻的宿主细胞。最近，SCFA一直是 被检测为对组蛋白的化学修饰，称为组蛋白酰基标记，表明一部分 这些代谢物进入核沉积到染色质上。虽然某些组蛋白酰基标记已经 据报道对转录进行了积极调节，包括良好的组蛋白乙酰化，机械 较新的酰基标记（例如组蛋白丁基化）的功能作用在很大程度上是未知的。此外，SCFA如何 在细胞中进行调节以进入核，并在染色质上作用不确定。在鼠标肠中， 组蛋白上的特定酰基修饰与微生物的存在正相关。此外， 抗生素处理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性的 在微生物群上。组蛋白酰基标记对微生物群的这种依赖性以组织特异性的方式发生 在小肠中观察到的最高差异，其中大小的肠相相交。现在我们的目标 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 鼠标肠道作为模型系统。我们假设SCFA被写入染色质上，作为组蛋白酰基化 受调节的方式，响应微生物环境介导关键的转录程序。到 解决了这一假设，基因调节中选择的组蛋白酰基标记的机械功能将是 通过将小鼠肠道用作研究这些组蛋白标记的模型进行了研究。此外， 微生物群依赖性染色质酰基标记和代谢产物将以全面的方式定义。 最后，还将确定由代谢酶调节组蛋白酰基标记。一起， 这些目标的完成将扩大我们对新型组蛋白标记的生理作用的理解，以及 还将提供有关微生物组如何影响染色质景观的机械洞察力。此外， 该建议将通过染色质读取器蛋白募集来阐明组蛋白酰基标记的功能 和下游转录调节。