Comparative transcriptome profiling of the injured zebrafish and mouse hearts identifies miRNA-dependent repair pathways.
Comparative transcriptome profiling of the injured zebrafish and mouse hearts identifies miRNA-dependent repair pathways.
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受伤的斑马鱼和小鼠心脏的比较转录组分析鉴定了miRNA依赖性修复途径。
DOI：
10.1093/cvr/cvw031
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发表时间：
2016-05-01
影响因子：
10.8
通讯作者：
Pedrazzini T
中科院分区：
文献类型：
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作者：
Crippa S;Nemir M;Ounzain S;Ibberson M;Berthonneche C;Sarre A;Boisset G;Maison D;Harshman K;Xenarios I;Diviani D;Schorderet D;Pedrazzini T
成年哺乳动物的心脏再生能力很差。相比之下，斑马鱼的心脏在成年后保持着强大的再生能力。这些不同的反应是受损心脏中进化保守的基因调控网络的不同利用的结果。为了系统地识别控制损伤后心脏修复的miRNA依赖网络，我们对成年小鼠和斑马鱼的心脏转录组进行了比较基因和miRNA分析。使用综合方法，我们发现45个mirna依赖网络，涉及关键的生物学途径，在受伤的斑马鱼和小鼠的心脏中被不同的调节。我们更具体地研究了mir -26a依赖性反应。因此，miR-26a在损伤后的鱼心脏中下调，而其在小鼠心脏中的表达保持不变。miR-26a的靶标涉及细胞周期的激活因子和Ezh2， Ezh2是多梳抑制复合体2 （PRC2）的一个组成部分。重要的是，PRC2对细胞周期的负调控因子具有抑制作用。因此，在培养的新生儿心肌细胞中，抑制miR-26a刺激心肌细胞增殖。因此，miR-26a敲低延长了出生后小鼠心脏心肌细胞的增殖窗口期。这种新策略确定了一系列mirna和相关途径，特别是miR-26a，它们代表了诱导损伤心脏修复的有吸引力的治疗靶点。
The adult mammalian heart has poor regenerative capacity. In contrast, the zebrafish heart retains a robust capacity for regeneration into adulthood. These distinct responses are consequences of a differential utilization of evolutionary-conserved gene regulatory networks in the damaged heart. To systematically identify miRNA-dependent networks controlling cardiac repair following injury, we performed comparative gene and miRNA profiling of the cardiac transcriptome in adult mice and zebrafish. Using an integrated approach, we show that 45 miRNA-dependent networks, involved in critical biological pathways, are differentially modulated in the injured zebrafish vs. mouse hearts. We study, more particularly, the miR-26a-dependent response. Therefore, miR-26a is down-regulated in the fish heart after injury, whereas its expression remains constant in the mouse heart. Targets of miR-26a involve activators of the cell cycle and Ezh2, a component of the polycomb repressive complex 2 (PRC2). Importantly, PRC2 exerts repressive functions on negative regulators of the cell cycle. In cultured neonatal cardiomyocytes, inhibition of miR-26a stimulates, therefore, cardiomyocyte proliferation. Accordingly, miR-26a knockdown prolongs the proliferative window of cardiomyocytes in the post-natal mouse heart. This novel strategy identifies a series of miRNAs and associated pathways, in particular miR-26a, which represent attractive therapeutic targets for inducing repair in the injured heart.