Epitranscriptional orchestration of genetic reprogramming is an emergent property of stress-regulated cardiac microRNAs
Epitranscriptional orchestration of genetic reprogramming is an emergent property of stress-regulated cardiac microRNAs
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DOI：
10.1073/pnas.1214996109
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发表时间：
2012-11-27
影响因子：
11.1
通讯作者：
Dorn, Gerald W., II
中科院分区：
文献类型：
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作者：
Hu, Yuanxin;Matkovich, Scot J.;Dorn, Gerald W., II
心脏应激反应是由一个进化保守的基因表达程序驱动的，该程序包含数十个microRNA和数百个mRNAs。人们正在研究不同个体microRNAs的功能，但应激调节的microRNAs和mRNAs之间相互作用的总体目的以及在microRNA介导的应激心脏表观遗传和传统转录遗传重新编程中可能扮演的不同角色尚不清楚。在这里，我们使用深度测序来询问压力超负荷的小鼠心脏中的microRNA和mRNA的调节，并对早期心肌肥厚期间的microRNA-mRNA的相互作用进行了全基因组检查。根据丰度和调节模式，心脏microRNAs可分为结构性表达的管家、调节的动态平衡或动态早期应激反应的microRNAs。对62个应激反应心脏microRNAs的调控只直接影响66mRNAs的水平，但microRNA介导的表观遗传调控的全球影响通过优先靶向编码转录因子、激酶和磷酸酶的mRNAs而被放大，这些mRNAs具有放大的次要作用。因此，应激调节的microRNAs的一个紧急合作特性是转录和翻译后事件的协调，这有助于确定应激反应心脏表型。这一全球功能解释了如何通过MicroRNAs对不断变化的生理环境进行动态感知和反应的microRNAs，通过适度的个体改变靶基因和蛋白质含量来诱导大的末端器官效应。
Cardiac stress responses are driven by an evolutionarily conserved gene expression program comprising dozens of microRNAs and hundreds of mRNAs. Functionalities of different individual microRNAs are being studied, but the overall purpose of interactions between stress-regulated microRNAs and mRNAs and potentially distinct roles for microRNA-mediated epigenetic and conventional transcriptional genetic reprogramming of the stressed heart are unknown. Here we used deep sequencing to interrogate microRNA and mRNA regulation in pressure-overloaded mouse hearts, and performed a genome-wide examination of microRNA-mRNA interactions during early cardiac hypertrophy. Based on abundance and regulatory patterns, cardiac microRNAs were categorized as constitutively expressed housekeeping, regulated homeostatic, or dynamic early stress-responsive microRNAs. Regulation of 62 stress-responsive cardiac microRNAs directly affected levels of only 66 mRNAs, but the global impact of microRNA-mediated epigenetic regulation was amplified by preferential targeting of mRNAs encoding transcription factors, kinases, and phosphatases exerting amplified secondary effects. Thus, an emergent cooperative property of stress-regulated microRNAs is orchestration of transcriptional and posttranslational events that help determine the stress-reactive cardiac phenotype. This global functionality explains how large end-organ effects can be induced through modest individual changes in target mRNA and protein content by microRNAs that sense and respond dynamically to a changing physiological milieu.