A long non-coding RNA (Lrap) modulates brain gene expression and levels of alcohol consumption in rats.
A long non-coding RNA (Lrap) modulates brain gene expression and levels of alcohol consumption in rats.
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长链非编码RNA（Lrap）调节大鼠大脑基因表达和酒精消耗水平。
DOI：
10.1111/gbb.12698
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Tabakoff B
中科院分区：
文献类型：
--
作者：
Saba LM;Hoffman PL;Homanics GE;Mahaffey S;Daulatabad SV;Janga SC;Tabakoff B
LncRNAs是转录组数量和质量特征的重要调节因子。我们使用QTL和其他统计分析来确定与饮酒相关的基因共表达模块。这个模块的“中枢基因”，LRAP(酒精偏好的长非编码RNA)，是一个类似于lncRNA的未注释的转录本。我们使用偏相关分析来确定LRAP是协同表达模块完整性的主要贡献者。利用CRISPR/Cas9技术，我们在Wistar大鼠中阻断了LRAP基因的一个外显子。对野生型、杂合型和基因敲除大鼠的酒精消费测量表明，LRAP的干扰导致了酒精消费/酒精偏好的增加。LRAP的中断还导致了700多个其他转录本的表达变化。此外，很明显，LRAP可能在受影响的转录本的选择性剪接中具有功能。在对差异表达的转录本进行的浓缩分析中，“对乙醇的反应”这一GO类别成为首选。我们验证了LRAP作为大鼠饮酒的调节因子的作用，也证实了LRAP作为大量脑转录的表达和剪接的修饰物。这些转录本的一个特定子集显著影响大鼠(可能还有人类)的酒精消费。我们的工作表明了基因组非编码元件的多效性，网络分析在识别影响表型的关键元件方面的能力，以及并不是所有由基因编辑产生的变化对伴随的表型变化都是关键的。LRAP是一种新的lncRNA，是酒精消费的媒介，也是脑RNA表达和剪接的修饰物。在LRAP+/+与LRAP−/−大鼠(A)的大脑差异表达转录本组中，丰富的GO和KEGG通路的类别。B和C绘制的热图显示了LRAP+/+、LRAP+/−和LRAP−/−大鼠之间“对乙醇的反应”(C)和“紧密连接”类别中所包括的基因表达差异的方向和程度。文中讨论了这些基因与LRAP基因修饰大鼠不同饮酒量之间的关系。
LncRNAs are important regulators of quantitative and qualitative features of the transcriptome. We have used QTL and other statistical analyses to identify a gene coexpression module associated with alcohol consumption. The “hub gene” of this module, Lrap (Long non‐coding RNA for alcohol preference), was an unannotated transcript resembling a lncRNA. We used partial correlation analyses to establish that Lrap is a major contributor to the integrity of the coexpression module. Using CRISPR/Cas9 technology, we disrupted an exon of Lrap in Wistar rats. Measures of alcohol consumption in wild type, heterozygous and knockout rats showed that disruption of Lrap produced increases in alcohol consumption/alcohol preference. The disruption of Lrap also produced changes in expression of over 700 other transcripts. Furthermore, it became apparent that Lrap may have a function in alternative splicing of the affected transcripts. The GO category of “Response to Ethanol” emerged as one of the top candidates in an enrichment analysis of the differentially expressed transcripts. We validate the role of Lrap as a mediator of alcohol consumption by rats, and also implicate Lrap as a modifier of the expression and splicing of a large number of brain transcripts. A defined subset of these transcripts significantly impacts alcohol consumption by rats (and possibly humans). Our work shows the pleiotropic nature of non‐coding elements of the genome, the power of network analysis in identifying the critical elements influencing phenotypes, and the fact that not all changes produced by genetic editing are critical for the concomitant changes in phenotype. Lrap, a novel lncRNA, is a mediator of alcohol consumption and a modifier of brain RNA expression and splicing. Categories from GO and KEGG pathways that are enriched within the group of differentially expressed transcripts in brains of the Lrap +/+ versus Lrap −/− rats (A). B and C depict heat maps illustrating the direction and magnitude of difference in expression of the genes included in the category “response to ethanol” (C) and “tight junction” between Lrap +/+, Lrap +/− and Lrap −/− rats. Relations between these genes and differential alcohol consumption of genetically, Lrap modified rats are discussed in the manuscript.
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影响因子：
4.7
作者：
Balla A;Dong B;Shilpa BM;Vemuri K;Makriyannis A;Pandey SC;Sershen H;Suckow RF;Vinod KY
通讯作者：
Vinod KY
影响因子：
14.9
作者：
The Gene Ontology Consortium
通讯作者：
The Gene Ontology Consortium
影响因子：
4.3
作者：
Franklin KM;Asatryan L;Jakowec MW;Trudell JR;Bell RL;Davies DL
通讯作者：
Davies DL
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
2.5
作者：
Harrall, Kylie K.;Kechris, Katerina J.;Tabakoff, Boris;Hoffman, Paula L.;Hines, Lisa M.;Tsukamoto, Hidekazu;Pravenec, Michal;Printz, Morton;Saba, Laura M.
通讯作者：
Saba, Laura M.