Deciphering the contribution of enhancer transcription to enhancer function
破译增强子转录对增强子功能的贡献
基本信息
- 批准号:10533734
- 负责人:
- 金额:$ 3.41万
- 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:2022-01-01 至 2023-09-22
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalATAC-seqAreaBindingBinding SitesBiological AssayBiologyCRISPR interferenceCell NucleusChromatinCoupledDNA SequenceDataDiseaseElementsEnhancersEnvironmentEventFellowshipFundingGene ActivationGenesGenetic Enhancer ElementGenetic TranscriptionGenomeGenomicsGoalsHealthHistone AcetylationIndividual National Research Service AwardInflammatoryKnock-outLearningLinkMacrophageMapsMeasurementMeasuresMediatingMessenger RNAModelingMolecularMolecular BiologyMolecular Biology TechniquesMusMutationNucleosomesPlasmidsPostdoctoral FellowProteinsRNARNA Polymerase IIRampRegulator GenesRegulatory ElementReporterResearchResearch DesignResolutionRoleScientistSignal PathwaySignal TransductionSiteStimulusStructureTechniquesTestingTextbooksTimeTrainingTranscriptTranscription InitiationTranscription Initiation SiteTranscriptional ActivationTranscriptional RegulationUniversitiesUntranslated RNAWorkgenetic variantin vivonext generation sequencingnovelpre-doctoralprogramspromoterrecruitresponseskillsthree dimensional structuretranscription factortransmission process
项目摘要
PROJECT SUMMARY/ABSTRACT
The applicant is requesting two years of support from a Ruth L. Kirschstein National Research Service Award
for Individual Predoctoral Fellowship to Promote Diversity in Health-Related Research (F31-Diversity) to examine
the relationship between enhancer transcription and enhancer function. Enhancers have been shown to initiate
short, non-coding transcripts in quantities rivaling promoters, yet their role on enhancer function remains
controversial. My preliminary data suggests that enhancers and promoters synchronize their activity to form co-
regulated domains. This result is surprising given that previous studies using total RNA measurements have
indicated that enhancer eRNAs ramp up before their associated mRNAs, suggesting that enhancers get
activated first and that this activation then gets transmitted to the associated promoters. Co-regulated domains
explain several of the mechanisms that the textbook model of enhancer function fails to. These include that
enhancer sequences are indistinguishable from promoters, that they are bound and initiate transcription by RNA
polymerase II, that enhancers and promoters form hubs in the nucleus, that enhancers act in an additive or
synergistic manner, and the redundancies observed when knocking out single enhancers in a multi-enhancer
locus. The goal of this research is to test the hypothesis that enhancers may function by serving as
simultaneously activated and mutually reinforcing transcription initiation sites within CRDs. This hypothesis
implies that enhancer transcription would be essential for enhancer function. I will test this hypothesis in three
specific aims: (1) determine the generality of enhancer-promoter co-regulatory domains across signaling
responses, to uncover whether the formation of co-regulated domains are a general regulatory mechanism
underlying signal response (2) determine the relationship between enhancer transcription and enhancer function
outside of their native genomic environment, to examine the relationship between enhancer transcription and
enhancer function outside of their native genomic context, and (3) determine the impact of silencing enhancer
transcription on gene activation in vivo, to determine the influence that shutting down enhancer transcription ahs
on enhancer function in its native genomic context. This training will allow me to (1) develop skills in the areas
of research design, analysis and interpretation using next-generation sequencing and molecular biology
techniques; (2) learn the fundamentals of molecular, chromatin, and enhancer biology; (3) successfully defend
a dissertation; and (4) obtain a competitive post-doctoral fellowship with the long-term goal to become a
successful, independently-funded scientist at a research-intensive university.
项目概要/摘要
申请人请求 Ruth L. Kirschstein 国家研究服务奖提供两年的支持
个人博士前奖学金以促进健康相关研究的多样性(F31-多样性)进行审查
增强子转录与增强子功能之间的关系。增强子已被证明可以启动
短的非编码转录本的数量与启动子相当,但它们对增强子功能的作用仍然存在
有争议的。我的初步数据表明增强子和启动子同步它们的活性以形成协同作用
受监管的领域。这一结果令人惊讶,因为之前使用总 RNA 测量的研究已经
表明增强子 eRNA 在其相关 mRNA 之前增加,这表明增强子得到
首先被激活,然后这种激活被传递到相关的启动子。共同监管领域
解释增强子功能教科书模型未能解释的几种机制。这些包括
增强子序列与启动子没有区别,它们与 RNA 结合并启动转录
聚合酶 II,增强子和启动子在细胞核中形成中枢,增强子以添加剂或
协同方式,以及敲除多增强子中的单个增强子时观察到的冗余
轨迹。这项研究的目的是检验增强子可能通过充当
CRD 内同时激活且相互增强的转录起始位点。这个假设
意味着增强子转录对于增强子功能至关重要。我将分三步检验这个假设
具体目标:(1)确定跨信号传导的增强子-启动子共同调控域的普遍性
反应,揭示共同调控域的形成是否是一种普遍的调控机制
底层信号反应(2)确定增强子转录与增强子功能之间的关系
在其天然基因组环境之外,检查增强子转录和
增强子在其天然基因组环境之外的功能,以及(3)确定沉默增强子的影响
转录对体内基因激活的影响,以确定关闭增强子转录的影响
关于其天然基因组环境中的增强子功能。这次培训将使我能够 (1) 培养以下领域的技能
使用下一代测序和分子生物学进行研究设计、分析和解释
技术; (2) 学习分子、染色质和增强子生物学的基础知识; (3) 成功卫冕
一篇论文; (4) 获得有竞争力的博士后奖学金,其长期目标是成为一名
研究密集型大学中成功的、独立资助的科学家。
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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Carlos Guzman其他文献
Carlos Guzman的其他文献
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{{ truncateString('Carlos Guzman', 18)}}的其他基金
Deciphering the contribution of enhancer transcription to enhancer function
破译增强子转录对增强子功能的贡献
- 批准号:
10316087 - 财政年份:2022
- 资助金额:
$ 3.41万 - 项目类别:
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