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miRNA 调控转录与易产生乙醇催眠作用的小鼠品系相关。

miRNA-regulated transcription associated with mouse strains predisposed to hypnotic effects of ethanol.

机构信息

Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado.

Department of Biostatistics and Informatics, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.

出版信息

Brain Behav. 2018 Jun;8(6):e00989. doi: 10.1002/brb3.989. Epub 2018 Apr 30.

DOI:10.1002/brb3.989
PMID:30106247
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5991579/
Abstract

INTRODUCTION

Studying innate sensitivity to ethanol can be an important first step toward understanding alcohol use disorders. In brain, we investigated transcripts, with evidence of miRNA modulation related to a predisposition to the hypnotic effect of ethanol, as measured by loss of righting reflex (LORR).

METHODS

Expression of miRNAs (12 samples) and expression of mRNAs (353 samples) in brain were independently analyzed for an association with LORR in mice from the LXS recombinant inbred panel gathered across several small studies. These results were then integrated via a meta-analysis of miRNA-mRNA target pairs identified in miRNA-target interaction databases.

RESULTS

We found 112 significant miRNA-mRNA pairs where a large majority of miRNAs and mRNAs were highly interconnected. Most pairs indicated a pattern of increased levels of miRNAs and reduced levels of mRNAs being associated with more alcohol-sensitive strains. For example, CaMKIIn1 was targeted by multiple miRNAs associated with LORR. CAMK2N1 is an inhibitor of CAMK2, which among other functions, phosphorylates, or binds to GABA and NMDA receptors.

CONCLUSIONS

Our results suggest a novel role of miRNA-mediated regulation of an inhibitor of CAMK2 and its downstream targets including the GABA and NMDA receptors, which have been previously implicated to have a role in ethanol-induced sedation and sensitivity.

摘要

简介

研究对乙醇的先天敏感性可以是理解酒精使用障碍的重要第一步。在大脑中，我们研究了与催眠作用的易感性相关的 miRNA 调节的转录本，催眠作用通过翻正反射（LORR）丧失来衡量。

方法

使用来自 LXS 重组近交系面板的小鼠的几个小型研究中收集的 LORR 分析脑内 miRNA（12 个样本）和 mRNA（353 个样本）的表达与 LORR 的相关性。然后通过 miRNA-mRNA 靶对的元分析整合这些结果识别在 miRNA-靶相互作用数据库中。

结果

我们发现了 112 个显著的 miRNA-mRNA 对，其中大多数 miRNA 和 mRNAs 高度相互连接。大多数对表明 miRNA 水平升高和 mRNAs 水平降低与更敏感的酒精菌株相关的模式。例如，CaMKIIn1 被与 LORR 相关的多个 miRNA 靶向。CAMK2N1 是 CAMK2 的抑制剂，除了其他功能外，CAMK2 还可以磷酸化或结合 GABA 和 NMDA 受体。

结论

我们的结果表明，miRNA 介导的 CAMK2 抑制剂及其下游靶标（包括 GABA 和 NMDA 受体）的调节具有新的作用，这些靶标先前被认为在乙醇诱导的镇静和敏感性中起作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dffd/5991579/4422b89c822d/BRB3-8-e00989-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dffd/5991579/3a68e748d9f6/BRB3-8-e00989-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dffd/5991579/f238280ac174/BRB3-8-e00989-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dffd/5991579/e11d70f69d73/BRB3-8-e00989-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dffd/5991579/cf135c2ba15d/BRB3-8-e00989-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dffd/5991579/4422b89c822d/BRB3-8-e00989-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dffd/5991579/3a68e748d9f6/BRB3-8-e00989-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dffd/5991579/f238280ac174/BRB3-8-e00989-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dffd/5991579/e11d70f69d73/BRB3-8-e00989-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dffd/5991579/cf135c2ba15d/BRB3-8-e00989-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dffd/5991579/4422b89c822d/BRB3-8-e00989-g005.jpg

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