Regulation of gene expression and genome organization by small RNAs
小RNA调控基因表达和基因组组织
基本信息
- 批准号:10407048
- 负责人:
- 金额:$ 44.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AffectBinding ProteinsCaenorhabditis elegansCellsCellular biologyCongenital AbnormalityCytoplasmic GranulesDevelopmental BiologyDiseaseEukaryotaGene ExpressionGene Expression RegulationGenerationsGenesGeneticGenetic TranscriptionGenomeGerm CellsGoalsHumanHuman BiologyHuman DevelopmentInfertilityMalignant NeoplasmsMessenger RNAMethylationMicroscopyNucleotidesPathway interactionsPhasePhosphorylationPhylogenyPlayPost-Transcriptional RegulationPost-Translational Protein ProcessingProteinsRNARNA DegradationRNA InterferenceRegulator GenesRegulatory PathwayRoleSmall RNASorting - Cell MovementSpecificityStructureSystemTimeTranscriptional RegulationTranslational RepressionWorkexperimental studygenome integrityhuman diseasetool
项目摘要
RNA silencing is a gene regulatory mechanism by which small RNAs (18-30 nucleotides) and their Argonaute
protein co-factors modulate the expression of both foreign and endogenous mRNAs. Small RNAs play a critical
role in maintaining proper gene expression by identifying fully or partially complementary mRNAs and targeting
them for either transcriptional or post-transcriptional regulation. The role of RNA silencing in gene regulatory
pathways is conserved across most eukaryotes and is thus of fundamental importance to the developmental and
cellular biology of humans. C. elegans is an excellent system to study RNA silencing because of its short
generation time, its transparency which is ideal for microscopy, and the powerful genetic tools available for
genome manipulation. In C. elegans germ cells, proteins involved in RNA silencing are organized into sub-
compartments of perinuclear condensates, with each sub-compartment playing a unique and critical role. Many
protein factors have been identified that localize to these structures, yet we know little about how they are
organized and assembled. In the first part of this proposal, we will identify factors and conditions that promote
assembly of RNA silencing components into perinuclear condensates. We will further identify the RNAs in each
sub-compartment, with the ultimate goal of dissecting the trajectory of a targeted mRNA through each of its
phases: beginning with transcription, continuing through this assemblage of perinuclear condensates, and
ultimately with translational repression or degradation by the RNA silencing pathway. Because there are ~27 C.
elegans Argonaute proteins, many of which colocalize at P granules, we will next identify the factors contributing
to sorting of small RNA into the appropriate Argonaute proteins. This sorting is critical because many Argonaute
proteins bind different small RNAs from one another, target distinct groups of mRNAs, and can have very
different regulatory effects on these target mRNAs. Finally, we will focus on how protein modifications such as
phosphorylation and methylation can regulate RNA silencing pathways, including affecting localization,
interacting partners, and dynamics of Argonaute proteins and other key factors. Together, the proposed
experiments will uncover the key details of how RNA silencing pathways are organized, how the specificity of
the pathways is defined, and what mechanisms regulate these pathways. This work will lead to a better
understanding of how small RNAs modulate gene expression in healthy cells, which can ultimately be applied to
discerning how changes in these pathways cause misregulation of genes in humans and transition to a disease
state.
RNA沉默是一种基因调控机制,小RNA(18-30个核苷酸)和它们的Argane
蛋白质共因子调节外源和内源mRNAs的表达。小RNA发挥着关键作用
通过识别完全或部分互补的mRNAs和靶向来维持适当的基因表达
它们对转录或转录后调节起作用。RNA沉默在基因调控中的作用
通路在大多数真核生物中是保守的,因此对发育和
人类的细胞生物学。线虫是研究RNA沉默的优秀系统,因为它很短
世代时间,其透明度,这是理想的显微镜,以及强大的遗传工具,可用于
基因组操纵。在线虫生殖细胞中,参与RNA沉默的蛋白质被组织成亚
由核周凝析油组成的隔室,每个隔室发挥着独特和关键的作用。许多
已经确定了定位于这些结构的蛋白质因子,但我们对它们是如何存在的知之甚少。
有条不紊地组织和组装。在这项提案的第一部分,我们将确定促进
将RNA沉默成分组装成核周缩合物。我们将进一步确定每个组件中的RNA
小室,最终目标是通过它的每一个
阶段:从转录开始,继续到这个核周冷凝物的组合,以及
最终通过RNA沉默途径进行翻译抑制或降解。因为有~27摄氏度。
其中许多蛋白共定位在P颗粒上,接下来我们将确定影响因素
将小的RNA分选成适当的ArgAerte蛋白。这种排序是至关重要的,因为许多阿戈宇航员
蛋白质相互结合不同的小RNA,靶向不同的mRNAs组,并且可以有非常
对这些靶向mRNA的不同调控作用。最后,我们将重点介绍蛋白质修饰是如何
磷酸化和甲基化可以调节RNA沉默途径,包括影响定位,
相互作用的伙伴,以及ArgAerte蛋白质的动态和其他关键因素。总而言之,建议的
实验将揭示RNA沉默途径是如何组织的、RNA沉默途径的特异性如何
定义了这些途径,以及调节这些途径的机制。这项工作将会带来更好的
了解小RNA如何调节健康细胞中的基因表达,这最终可以应用于
辨别这些通路的变化如何导致人类基因的错误调节和向疾病的转变
州政府。
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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Carolyn Marie Phillips其他文献
Carolyn Marie Phillips的其他文献
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{{ truncateString('Carolyn Marie Phillips', 18)}}的其他基金
Regulation of gene expression and genome organization by small RNAs
小RNA调控基因表达和基因组组织
- 批准号:
10613546 - 财政年份:2016
- 资助金额:
$ 44.14万 - 项目类别:
Regulation of gene expression and genome organization by small RNAs
小RNA调控基因表达和基因组组织
- 批准号:
9330900 - 财政年份:2016
- 资助金额:
$ 44.14万 - 项目类别:
Regulation of gene expression and genome organization by small RNAs
小RNA调控基因表达和基因组组织
- 批准号:
9977251 - 财政年份:2016
- 资助金额:
$ 44.14万 - 项目类别:
Regulation of gene expression and genome organization by small RNAs
小RNA调控基因表达和基因组组织
- 批准号:
10797485 - 财政年份:2016
- 资助金额:
$ 44.14万 - 项目类别:
Regulation of gene expression and genome organization by small RNAs
小RNA调控基因表达和基因组组织
- 批准号:
10389042 - 财政年份:2016
- 资助金额:
$ 44.14万 - 项目类别:
Regulation of gene expression and genome organization by small RNAs
小RNA调控基因表达和基因组组织
- 批准号:
9489282 - 财政年份:2016
- 资助金额:
$ 44.14万 - 项目类别:
Regulation of gene expression and genome organization by small RNAs
小RNA调控基因表达和基因组组织
- 批准号:
10726947 - 财政年份:2016
- 资助金额:
$ 44.14万 - 项目类别:
Regulation of gene expression and genome organization by small RNAs
小RNA调控基因表达和基因组组织
- 批准号:
10202138 - 财政年份:2016
- 资助金额:
$ 44.14万 - 项目类别:
Regulation of gene expression and genome organization by small RNAs
小RNA调控基因表达和基因组组织
- 批准号:
10621097 - 财政年份:2016
- 资助金额:
$ 44.14万 - 项目类别:
Silencing of Mobile Genetic Elements by Small RNAs
小RNA沉默移动遗传元件
- 批准号:
8565082 - 财政年份:2014
- 资助金额:
$ 44.14万 - 项目类别:
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