Genetic Models Reveal cis and trans Immune-Regulatory Activities for lincRNA-Cox2.
Genetic Models Reveal cis and trans Immune-Regulatory Activities for lincRNA-Cox2.
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DOI：
10.1016/j.celrep.2018.10.027
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发表时间：
2018-11-06
期刊：
影响因子：
8.8
通讯作者：
Carpenter S
中科院分区：
文献类型：
--
作者：
Elling R;Robinson EK;Shapleigh B;Liapis SC;Covarrubias S;Katzman S;Groff AF;Jiang Z;Agarwal S;Motwani M;Chan J;Sharma S;Hennessy EJ;FitzGerald GA;McManus MT;Rinn JL;Fitzgerald KA;Carpenter S
可诱导的基因表达程序是宿主炎症反应的标志。最近，长的基因间非编码RNA(LincRNAs)被证明可以调节这些反应的幅度、持续时间和分辨率。其中包括lincRNA-COX2，这是一种动态调节的基因，广泛控制免疫基因的表达。为了评估这种lincRNA的体内功能，我们对lincRNA-COX2缺陷小鼠的多种模型进行了鉴定。缺乏lincRNA-COX2的巨噬细胞和小鼠组织改变了炎症基因的表达。对不同组织的转录研究表明，lincRNA-COX2基因的缺失也强烈地削弱了邻近基因前列腺素-过氧化物合酶(Ptgs2)的基础和诱导表达，Ptgs2编码前列腺素生物合成途径中的关键酶-环氧合酶-2。通过利用体外和体内不同的遗传操作，我们发现lincRNA-COX2通过增强子RNA机制来调节Ptgs2。更重要的是，lincRNA-COX2也独立于Ptgs2在反式转录中发挥作用，在体内调节关键的先天性免疫基因。Elling等人。利用一系列的lincRNA-COX2遗传模型表明，lincRNA-COX2可以通过增强子RNA机制调节其邻近基因Ptgs2(COX2)。他们产生了一只lincRNA-COX2剪接缺陷的小鼠，并证实了lincRNA-COX2在脂多糖诱导的内毒素休克后反式调节免疫基因的功能。
An inducible gene expression program is a hallmark of the host inflammatory response. Recently, long intergenic non-coding RNAs (lincRNAs) have been shown to regulate the magnitude, duration, and resolution of these responses. Among these is lincRNA- Cox2, a dynamically regulated gene that broadly controls immune gene expression. To evaluate the in vivo functions of this lincRNA, we characterized multiple models of lincRNA-Cox2-deficient mice. LincRNA- Cox2-deficient macrophages and murine tissues had altered expression of inflammatory genes. Tran- scriptomic studies from various tissues revealed that deletion of the lincRNA-Cox2 locus also strongly impaired the basal and inducible expression of the neighboring gene prostaglandin-endoperoxide synthase (Ptgs2), encoding cyclooxygenase-2, a key enzyme in the prostaglandin biosynthesis pathway. By utilizing different genetic manipulations in vitro and in vivo, we found that lincRNA-Cox2 functions through an enhancer RNA mechanism to regulate Ptgs2. More importantly, lincRNA-Cox2 also functions in trans, independently of Ptgs2, to regulate critical innate immune genes in vivo. Elling et al. utilize a number of lincRNA- Cox2 genetic models to show that lincRNA-Cox2 can regulate its neighboring gene Ptgs2 (Cox2) through an enhancer RNA mechanism. They generate a lincRNA-Cox2 splicing- deficient mouse and confirm that lincRNA-Cox2 functions in trans to regulate immune genes following LPS- induced endotoxic shock.
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影响因子：
64.5
作者：
Gomez JA;Wapinski OL;Yang YW;Bureau JF;Gopinath S;Monack DM;Chang HY;Brahic M;Kirkegaard K
通讯作者：
Kirkegaard K
影响因子：
8.8
作者：
Groff AF;Sanchez-Gomez DB;Soruco MML;Gerhardinger C;Barutcu AR;Li E;Elcavage L;Plana O;Sanchez LV;Lee JC;Sauvageau M;Rinn JL
通讯作者：
Rinn JL
DOI：
10.1126/science.1240925
发表时间：
2013-08-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Carpenter S;Aiello D;Atianand MK;Ricci EP;Gandhi P;Hall LL;Byron M;Monks B;Henry-Bezy M;Lawrence JB;O'Neill LA;Moore MJ;Caffrey DR;Fitzgerald KA
通讯作者：
Fitzgerald KA
DOI：
10.1126/science.1237973
发表时间：
2013-08-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Engreitz JM;Pandya-Jones A;McDonel P;Shishkin A;Sirokman K;Surka C;Kadri S;Xing J;Goren A;Lander ES;Plath K;Guttman M
通讯作者：
Guttman M
影响因子：
3.5
作者：
Cooper DR;Carter G;Li P;Patel R;Watson JE;Patel NA
通讯作者：
Patel NA