A novel class of long non-coding RNA in regulation of the type I interferonresponse
一类新型长非编码RNA调节I型干扰素反应
基本信息
- 批准号:10535470
- 负责人:
- 金额:$ 5.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAntiviral ResponseArchitectureAutoimmune DiseasesBiological AssayCell NucleusCellsCellular StressChIP-seqChromatinChromatin LoopChromatin ModelingClustered Regularly Interspaced Short Palindromic RepeatsCodeComplexDefense MechanismsEpigenetic ProcessEquilibriumGene ExpressionGenesGeneticGenetic TranscriptionGenomeGuide RNAHomeostasisHuman GenomeInfectionInterferon ActivationInterferon Type IInterferon-betaInterferonsKnock-in MouseMalignant NeoplasmsMeasuresMediatingModelingMolecularMusNatural ImmunityNucleic AcidsOrganismPhenotypePhysiologicalPost-Transcriptional RNA ProcessingProcessProteinsRNARecombinant Interferon BetaRegulationRoleSerumSignal TransductionSystemSystemic Lupus ErythematosusTestingTherapeuticTissuesTranscriptTransgenic MiceTransposaseUntranslated RNAVesicular stomatitis Indiana virusViralViral GenesVirus DiseasesVirus Replicationantiviral immunitychromatin remodelingchromosome conformation capturegenome editinggenomic locushistone modificationhuman diseaseimmune activationimmunopathologyimprovedin vivoinnate immune sensinginsightknock-downmammalian genomenovelposttranscriptionalprogramsresponsesenescencestressortranscriptomeviral resistance
项目摘要
Project Summary
The mammalian genome is pervasively transcribed to generate a complex non-coding transcriptome. A novel
class of long non-coding RNA (lncRNA) called DoGs for “Downstream-of-Gene”-containing transcripts was
recently discovered. In response to various stressors such as viral infections, DoG RNAs are expressed by
readthrough transcription that continues past the ends of some protein-coding genes for at least 5kb. Remarkably,
this previously unknown RNA species as a group accounts for up to 30% of all intergenic transcripts, yet their
function remains completely unknown. I discovered that innate immune sensing of viral nucleic acids and
activation of the type I interferon (IFN) antiviral response leads to expression of DoG RNAs from thousands of
genes, most notably from the IFN gene itself. I therefore hypothesize that a DoG RNA may function to
regulate its upstream gene of origin, and that this is an essential regulatory process in innate antiviral
responses. Mechanistically I propose that a DoG RNA remodels the chromatin and/or transcriptional
landscape of its upstream gene to achieve a poised state. This would be beneficial for organisms because
rapid responses to viral infections can be achieved. In Aim 1, I will evaluate the role of the DoG RNA from the
Ifnb1 gene (Ifnb1-DoG RNA) in regulating IFN-β expression using genetic, transcriptional, and post-
transcriptional approaches to manipulate DoG RNA levels. In Aim 2, I will investigate the molecular basis of
Ifnb1-DoG RNA function by characterizing the chromatin and transcriptional landscape of the Ifnb1 gene locus.
I will test whether DoG RNA expression affects post-transcriptional processing, epigenetic marks, and chromatin
architecture. In Aim 3, I will determine the physiological importance of DoG RNA in vivo. I will generate Ifnb1-
DoG RNA deficient mice by first generating guide RNA knock-in mice that targets downstream of Ifnb1 and then
by crossing these with dCas9 transgenic mice. I will study the effect of the Ifnb1-DoG RNA on innate immunity
at homeostasis and during viral infections with these mice. The type I IFN response is a critical component of
our antiviral defense mechanism, but can lead to human disease such as type I interferonopathies and systemic
lupus erythematosus when dysregulated. This study aims to advance our understanding of type I IFN regulation
by functionally characterizing a novel class of lncRNAs. Insights gained from this study can potentially be
leveraged to develop improved therapeutics for infectious and IFN-mediated autoimmune diseases.
项目摘要
哺乳动物基因组被普遍转录以产生复杂的非编码转录组。一种新型
一类称为DoG的长链非编码RNA(lncRNA)含有“基因下游”转录物,
最近发现的。响应于各种应激源,如病毒感染,DoG RNA通过以下途径表达:
在某些蛋白质编码基因的末端继续至少5 kb的通读转录。值得注意的是,
这种以前未知的RNA种类作为一个群体占所有基因间转录物的30%,但它们的
功能仍然完全未知。我发现先天免疫感应病毒核酸和
I型干扰素(IFN)抗病毒应答的激活导致来自数千个细胞的DoG RNA的表达,
基因,尤其是IFN基因本身。因此,我假设DoG RNA的功能可能是
调节其上游基因的起源,这是一个重要的调控过程,在先天性抗病毒
应答从机制上讲,我认为DoG RNA重塑了染色质和/或转录水平,
其上游基因的景观,以达到一个平衡的状态。这对生物体是有益的,因为
可以实现对病毒感染的快速反应。在目标1中,我将评估来自于细胞的DoG RNA的作用。
Ifnb 1基因(Ifnb 1-DoG RNA)在IFN-β表达调控中的作用
转录方法来操纵DoG RNA水平。在目标2中,我将研究
Ifnb 1-DoG RNA通过表征Ifnb 1基因位点的染色质和转录景观来发挥功能。
我将测试DoG RNA表达是否影响转录后加工、表观遗传标记和染色质
架构在目标3中,我将确定DoG RNA在体内的生理重要性。我将生成Ifnb 1-
通过首先产生靶向Ifnb 1下游的指导RNA敲入小鼠,然后
通过将这些小鼠与dCas 9转基因小鼠杂交。我将研究Ifnb 1-DoG RNA对先天免疫的影响
在体内平衡和病毒感染期间。I型IFN应答是免疫应答的关键组成部分。
我们的抗病毒防御机制,但可以导致人类疾病,如I型干扰素病和系统性
红斑狼疮时失调。本研究旨在进一步了解I型干扰素的调控
通过对一类新的lncRNA进行功能表征。从这项研究中获得的见解可能是
用于开发针对感染性和IFN介导的自身免疫性疾病的改进疗法。
项目成果
期刊论文数量(0)
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专利数量(0)
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{{ truncateString('Annsea Park', 18)}}的其他基金
A novel class of long non-coding RNA in regulation of the type I interferonresponse
一类新型长非编码RNA调节I型干扰素反应
- 批准号:
10397979 - 财政年份:2021
- 资助金额:
$ 5.1万 - 项目类别:
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