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.
项目概要
哺乳动物基因组普遍转录以产生复杂的非编码转录组。一本小说
一类称为 DoG 的长非编码 RNA (lncRNA),用于包含“基因下游”的转录本
最近发现的。为了应对病毒感染等各种应激源,DoG RNA 通过以下方式表达:
通读转录,持续超过某些蛋白质编码基因的末端至少 5kb。值得注意的是,
这种以前未知的 RNA 物种作为一个群体占所有基因间转录本的 30%,但它们的
功能仍然完全未知。我发现病毒核酸的先天免疫感应和
I 型干扰素 (IFN) 抗病毒反应的激活导致数千个细胞中 DoG RNA 的表达
基因,最显着的是来自 IFN 基因本身。因此我推测 DoG RNA 的功能可能是
调节其上游起源基因,这是先天抗病毒的重要调节过程
回应。从机制上讲,我建议 DoG RNA 重塑染色质和/或转录
使其上游基因景观达到平衡状态。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 DoG RNA 的作用
Ifnb1 基因 (Ifnb1-DoG RNA) 通过遗传、转录和后转录调控 IFN-β 表达
操纵DoG RNA水平的转录方法。在目标 2 中,我将研究其分子基础
Ifnb1-DoG RNA 通过表征 Ifnb1 基因座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
建筑学。在目标 3 中,我将确定 DoG RNA 在体内的生理重要性。我将生成 Ifnb1-
DoG RNA 缺陷小鼠首先生成靶向 Ifnb1 下游的指导 RNA 敲入小鼠,然后
通过将这些小鼠与 dCas9 转基因小鼠杂交。我将研究 Ifnb1-DoG RNA 对先天免疫的影响
在这些小鼠的体内平衡和病毒感染期间。 I 型干扰素反应是
我们的抗病毒防御机制,但可能导致人类疾病,例如 I 型干扰素病和全身性疾病
失调时患红斑狼疮。本研究旨在增进我们对 I 型干扰素调节的理解
通过对一类新型 lncRNA 进行功能表征。从这项研究中获得的见解可能会
用于开发针对传染性和干扰素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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{{ 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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