Unexpected complexity in bacterial genomes
细菌基因组的意外复杂性
基本信息
- 批准号:10334351
- 负责人:
- 金额:$ 42.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:3&apos Untranslated Regions5&apos Untranslated RegionsBacterial GenomeBindingBinding SitesCellsCodeComplexDNA SequenceDNA-Directed RNA PolymeraseDataEscherichia coliEventGene ExpressionGene Expression RegulationGenesGeneticGenetic TranscriptionGenomicsIndividualIntercistronic RegionMapsMessenger RNAMolecular BiologyOpen Reading FramesOperonPaperProcessProteinsRNARegulationResearchRho FactorRibosomal RNARoleSiteTextbooksTransfer RNAUntranslated RNAWorkantiterminationattenuationfitnessin vivointerestprematurepromoterrhotermination factortranscription factor
项目摘要
SUMMARY
The textbook view of bacterial genomes shows a set of discrete genes, transcribed individually or as operons.
Transcription initiates at promoters upstream of these genes/operons, producing mostly protein-coding mRNAs
along with a smaller number of stable, functional RNAs (tRNAs, rRNAs, sRNAs). Transcription factors bind close
to promoters and regulate transcription from those promoters. Transcription terminates downstream of genes, in
3’ UTRs. This view has been the basis for decades of work on gene expression and gene regulation, with
enormous advances in our understanding of these processes. However, work from my group and others has
shown that bacterial genomes are far more complex. We will leverage my expertise in genetics, genomics, and
molecular biology, to continue productive lines of research on four overlapping topics that relate to the major
research focus of my group: the unexpected complexity of bacterial genomes. My lab has been very
productive on this topic, with 19 papers since 2016 directly relevant to the four themes described in this proposal.
Topic #1. Pervasive transcription. We and others have shown that most bacterial promoters are not in
intergenic regions, upstream of genes. Rather, they are located within genes, in sense or antisense orientations,
and are involved in “pervasive transcription”, whereby short, non-coding RNAs are transcribed before being
rapidly terminated by Rho and degraded. The majority of these RNAs are believed to be non-functional, and
suppression of pervasive transcription is required to maintain cell fitness.
Topic #2. Non-canonical transcription factor (TF) binding. We have mapped the direct and indirect regulatory
targets of hundreds of TFs across a wide range of bacterial species. Most TF binding sites are located within
genes, not intergenic regions. Moreover, most TF binding events are not associated with detectable regulation
of a nearby gene. Our data also show that in vivo binding profiles are often not well explained by a DNA sequence
motif, suggesting a role for other factors in determining the genomic sites of TF binding.
Topic #3. Widespread gene regulation by attenuation. We have shown that transcription of many Escherichia
coli genes is prematurely terminated by the conserved termination factor Rho, either in the 5’ UTR or ORF, a
process commonly referred to as “attenuation”. Attenuation has been described previously, but our data indicate
that it happens on a much larger scale than previously appreciated. We are interested in the mechanisms of
attenuation involving Rho termination, with a particular focus on the role of upstream ORFs (uORFs) that function
as cis-acting regulators, since we have identified large numbers of these ORFs in diverse bacterial species.
Topic #4. Processive antitermination. RNA polymerase can be protected from the action of the Rho
termination factor in a process known as “processive antitermination”. We will identify new regulatory targets of
known antiterminator proteins, we will determine the mechanisms of antitermination, and we will discover new
antiterminator proteins.
摘要
教科书上对细菌基因组的看法显示了一组独立的基因,单独转录或作为操纵子转录。
转录起始于这些基因/操纵子上游的启动子,主要产生编码蛋白质的mRNAs
以及数量较少的稳定的、有功能的RNA(tRNAs、rRNAs、sRNAs)。转录因子结合紧密
启动子和调控这些启动子的转录。转录终止于基因下游,在
3‘UTRs。这一观点是几十年来基因表达和基因调控工作的基础,
在我们对这些过程的理解方面取得了巨大的进步。然而,我的团队和其他人的工作已经
表明细菌基因组要复杂得多。我们将利用我在遗传学、基因组学和
分子生物学,继续在与主要学科相关的四个重叠主题上进行富有成效的研究
我的团队的研究重点是:细菌基因组出人意料的复杂性。我的实验室一直非常
自2016年以来,已有19篇论文与本提案所述的四个主题直接相关。
话题1.无处不在的转录。我们和其他人已经证明,大多数细菌启动子不在
基因上游的基因间隔区。相反,它们位于基因内,以正义或反义方向,
参与“普遍转录”,即短的、非编码的RNA在被转录之前被转录
被Rho迅速终止并降级。这些RNA中的大多数被认为是不起作用的,并且
抑制普遍转录是维持细胞适合性所必需的。
话题2.非规范转录因子(TF)结合。我们已经绘制了直接和间接监管
针对各种细菌种类的数百种生物因子。大多数转铁蛋白结合位点位于
基因,而不是基因间隔区。此外,大多数转铁蛋白结合事件与可检测的调控无关
附近的一个基因。我们的数据还表明,体内的结合图谱通常不能很好地用DNA序列来解释
基序,暗示了其他因素在确定Tf结合的基因组位置中的作用。
话题3:通过衰减进行广泛的基因调控。我们已经证明了许多大肠杆菌的转录
Coli基因被保守的终止因子Rho过早终止,在5‘UTR或ORF中,a
这一过程通常被称为“衰减”。衰减之前已经描述过了,但我们的数据表明
它发生的规模比之前想象的要大得多。我们对这些机制很感兴趣
涉及RHO终止的衰减,特别关注起作用的上游ORF(UORF)的作用
作为顺式作用的调节因子,因为我们已经在不同的细菌物种中发现了大量的这些ORF。
话题4.循序渐进的反堕胎。RNA聚合酶可以被保护而不受Rho的作用
终止因素在一个被称为“渐进反终止”的过程中。我们将确定新的监管目标
已知的抗终止蛋白,我们将确定抗终止的机制,并将发现新的
抗终止子蛋白。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Joseph Thomas Wade其他文献
Joseph Thomas Wade的其他文献
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{{ truncateString('Joseph Thomas Wade', 18)}}的其他基金
STnc520, a virulence-associated regulatory RNA in Salmonella Typhimurium
STnc520,鼠伤寒沙门氏菌毒力相关的调节 RNA
- 批准号:
10307637 - 财政年份:2020
- 资助金额:
$ 42.96万 - 项目类别:
High-throughput application of CRISPR technology to identify gene function in Salmonella
高通量应用CRISPR技术鉴定沙门氏菌基因功能
- 批准号:
9172073 - 财政年份:2016
- 资助金额:
$ 42.96万 - 项目类别:
HTS assay development for bacterial transcription factors
细菌转录因子的 HTS 检测开发
- 批准号:
8436800 - 财政年份:2013
- 资助金额:
$ 42.96万 - 项目类别:
HTS assay development for bacterial transcription factors
细菌转录因子的 HTS 检测开发
- 批准号:
8739660 - 财政年份:2013
- 资助金额:
$ 42.96万 - 项目类别:
Characterization of a novel ETEC virulence regulator
新型 ETEC 毒力调节剂的表征
- 批准号:
8232038 - 财政年份:2011
- 资助金额:
$ 42.96万 - 项目类别:
Characterization of a novel ETEC virulence regulator
新型 ETEC 毒力调节剂的表征
- 批准号:
8091726 - 财政年份:2011
- 资助金额:
$ 42.96万 - 项目类别:
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