Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs.
Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs.
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DOI：
10.1093/eurheartj/ehu180
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发表时间：
2015-02-07
影响因子：
39.3
通讯作者：
Pedrazzini T
中科院分区：
文献类型：
--
作者：
Ounzain S;Micheletti R;Beckmann T;Schroen B;Alexanian M;Pezzuto I;Crippa S;Nemir M;Sarre A;Johnson R;Dauvillier J;Burdet F;Ibberson M;Guigó R;Xenarios I;Heymans S;Pedrazzini T
心脏病被认为是心脏基因调控网络失调的结果。以前，这种网络的未被重视的组成部分是长链非编码RNA（lncRNA）。它们在心脏中的作用仍有待阐明。因此，本研究旨在系统地描述心肌梗死后心脏长非编码转录组的特征，并阐明其在心脏稳态中的潜在作用。我们通过RNA测序和从头转录重建注释了心肌梗死后的小鼠转录组，并整合了全基因组方法将特异性lncRNA与发育过程和生理参数相关联。特异性lncRNA的表达与心脏尺寸和功能的定义参数密切相关。使用染色质图谱来推断lncRNA功能，我们确定了许多在心脏发生和病理重塑中具有潜在作用的基因。绝大多数与活性心脏特异性增强剂有关。更重要的是，利昔单抗介导的敲低涉及新的lncRNA控制参与心脏发生的关键调控蛋白的表达。最后，我们确定了数百个人类直系同源基因，并证明特定的候选人在人类心脏病中受到差异调节。这些发现揭示了数百种新的心脏特异性lncRNA，它们具有与适应不良重塑、心脏功能和可能的心脏再生相关的独特调控和功能特征。这类新的分子代表了心脏疾病的潜在治疗靶点。此外，它们与心脏生理学的密切相关性使它们成为临床上有吸引力的候选生物标志物。
Heart disease is recognized as a consequence of dysregulation of cardiac gene regulatory networks. Previously, unappreciated components of such networks are the long non-coding RNAs (lncRNAs). Their roles in the heart remain to be elucidated. Thus, this study aimed to systematically characterize the cardiac long non-coding transcriptome post-myocardial infarction and to elucidate their potential roles in cardiac homoeostasis. We annotated the mouse transcriptome after myocardial infarction via RNA sequencing and ab initio transcript reconstruction, and integrated genome-wide approaches to associate specific lncRNAs with developmental processes and physiological parameters. Expression of specific lncRNAs strongly correlated with defined parameters of cardiac dimensions and function. Using chromatin maps to infer lncRNA function, we identified many with potential roles in cardiogenesis and pathological remodelling. The vast majority was associated with active cardiac-specific enhancers. Importantly, oligonucleotide-mediated knockdown implicated novel lncRNAs in controlling expression of key regulatory proteins involved in cardiogenesis. Finally, we identified hundreds of human orthologues and demonstrate that particular candidates were differentially modulated in human heart disease. These findings reveal hundreds of novel heart-specific lncRNAs with unique regulatory and functional characteristics relevant to maladaptive remodelling, cardiac function and possibly cardiac regeneration. This new class of molecules represents potential therapeutic targets for cardiac disease. Furthermore, their exquisite correlation with cardiac physiology renders them attractive candidate biomarkers to be used in the clinic.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
56.9
作者：
Carninci, P;Kasukawa, T;Hayashizaki, Y
通讯作者：
Hayashizaki, Y
影响因子：
12.3
作者：
Marques AC;Hughes J;Graham B;Kowalczyk MS;Higgs DR;Ponting CP
通讯作者：
Ponting CP
影响因子：
23.9
作者：
Cui K;Zang C;Roh TY;Schones DE;Childs RW;Peng W;Zhao K
通讯作者：
Zhao K
影响因子：
56.9
作者：
Latos, Paulina A.;Pauler, Florian M.;Barlow, Denise P.
通讯作者：
Barlow, Denise P.