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N6-methyladenosine-dependent regulation of bacterial development

N6-甲基腺苷依赖性细菌发育调节

基本信息

批准号：
1714539
负责人：
Lyle Simmons
金额：
$ 69万
依托单位：
Regents of the University of Michigan - Ann Arbor
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2022-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1714539&HistoricalAwards=false
关键词：
N6 methyladenosine dependent regulation bacterial

项目摘要

The overall goal of this project is to understand how naturally occurring chemical modifications of DNA influence information processing and the subsequent cellular response. All living organisms contain DNA, the genetic material that serves as the blueprint for life. DNA from diverse organisms, such as bacteria and humans, has chemical modifications that affect how the encoded information is read. One such modification is methyladenosine. Methyladenosine is commonly found in bacterial DNA and can change how cells process information by altering the genes that are switched on, which in turn can help the cell respond to changes in nutrient availability. This research examines a previously unstudied protein that forms methyladenosine in bacteria. When this protein is inactive and adenosine methylation is lost, cells undergo substantial changes in gene activity that affect how the cells develop and behave. This research benefits society by determining how methyladenosine influences bacterial development, including the formation of multicellular bacterial structures and distinct cell types that can affect antibiotic resistance. In addition to the research benefits, further societal impacts of this project include teaching the expanding field of computational biology to students from socioeconomically disadvantaged backgrounds. The project's outreach initiative provides high school students in rural Northern Michigan with the opportunity to learn introductory bioinformatics using an online educational portal developed as part of this research. Further, this project provides training opportunities for the next generation of scientists at both the undergraduate and graduate levels with specialized training in cutting edge sequencing approaches and methods of data analysis. The genomes of organisms from all three domains of life are known to harbor chemical modifications in the form of DNA methylation. N6-methyladenosine (m6A) is a type of modification detected in prokaryotic and some eukaryotic genomes. Although m6A methyltransferases, the enzymes responsible for genomic m6A, are found in many diverse bacterial species the function of m6A remains largely unstudied. The goal of this project is to understand the effects of genomic m6A modifications in the Gram-positive bacterium Bacillus subtilis. Initial experiments have shown that elimination of m6A from the B. subtilis genome results in the expression of genes involved in bacterial developmental processes. Moving forward, this research project will investigate the mechanism by which m6A affects the expression of genes involved in bacterial cell developmental transitions. Global genomics approaches will be used to determine the differences in bacterial chromosome structure, genome-wide protein landscapes, and gene expression upon loss of m6A. Further, targeted biochemical approaches will be used to determine if m6A is necessary and sufficient for differential gene expression and to identify the factors that respond to m6A in DNA regulatory regions. Once complete, this project will provide a mechanistic understanding for how m6A-dependent changes in gene expression interface with bacterial developmental platforms.

这个项目的总体目标是了解自然发生的DNA化学修饰如何影响信息处理和随后的细胞反应。所有活着的有机体都含有DNA，这是一种遗传物质，是生命的蓝图。来自细菌和人类等不同生物的DNA具有影响编码信息阅读方式的化学修饰。一种这样的修饰是甲基腺苷。甲基腺苷通常存在于细菌DNA中，可以通过改变被激活的基因来改变细胞处理信息的方式，这反过来又可以帮助细胞对营养供应的变化做出反应。这项研究检查了一种以前没有研究过的蛋白质，它在细菌中形成甲基腺苷。当这种蛋白质不活跃，腺苷甲基化丢失时，细胞的基因活性就会发生实质性的变化，从而影响细胞的发育和行为。这项研究通过确定甲基腺苷如何影响细菌发育，包括可能影响抗生素耐药性的多细胞细菌结构和不同细胞类型的形成，从而使社会受益。除了研究方面的好处，该项目的进一步社会影响还包括向来自社会经济贫困背景的学生教授不断扩大的计算生物学领域。该项目的推广活动为密歇根州北部农村的高中生提供了学习生物信息学入门知识的机会，该门户网站是作为本研究的一部分开发的。此外，该项目为下一代本科生和研究生科学家提供了培训机会，他们接受了尖端测序途径和数据分析方法方面的专门培训。所有三个生命领域的生物体的基因组都已知含有DNA甲基化形式的化学修饰。N6-甲基腺苷(M6A)是在原核生物和一些真核生物基因组中发现的一种修饰。虽然m6A甲基转移酶是负责基因组m6A的酶，但在许多不同的细菌物种中都发现了m6A甲基转移酶，但m6A的功能在很大程度上仍未被研究。该项目的目标是了解基因组m6A修饰对革兰氏阳性杆菌枯草芽孢杆菌的影响。初步实验表明，从枯草杆菌基因组中消除m6A会导致参与细菌发育过程的基因表达。展望未来，这项研究项目将探索m6A影响细菌细胞发育过渡相关基因表达的机制。全球基因组学方法将被用来确定细菌染色体结构、全基因组蛋白质图谱和m6A缺失后基因表达的差异。此外，将使用有针对性的生化方法来确定m6A对于差异基因表达是否必要和充分，并在DNA调节区确定对m6A做出反应的因素。一旦完成，这个项目将提供一个机制上的理解，即依赖于m6A的基因表达变化如何与细菌发育平台相互作用。