From the Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (E.E.C., A.B., H.W.M.D., I.M., N.E.G., M.E.A., C.R.B., Y.M.P.); Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.P.U., R.E., R.A.); National Heart and Lung Institute, Imperial College, London, United Kingdom (S.A.C.); Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany (N.H.); and Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (J.V.).
Circ Res. 2016 Feb 5;118(3):433-8. doi: 10.1161/CIRCRESAHA.115.307082. Epub 2015 Dec 15.
Alternative cleavage and polyadenylation (APA) of mRNA represents a layer of gene regulation that to date has remained unexplored in the heart. This phenomenon may be relevant, as the positioning of the poly(A) tail in mRNAs influences the length of the 3'-untranslated region (UTR), a critical determinant of gene expression.
To investigate whether the 3'UTR length is regulated by APA in the human heart and whether this changes in the failing heart.
We used 3'end RNA sequencing (e3'-Seq) to directly measure global patterns of APA in healthy and failing human heart specimens. By monitoring polyadenylation profiles in these hearts, we identified disease-specific APA signatures in numerous genes. Interestingly, many of the genes with shortened 3'UTRs in heart failure were enriched for functional groups such as RNA binding, whereas genes with longer 3'UTRs were enriched for cytoskeletal organization and actin binding. RNA sequencing in a larger series of human hearts revealed that these APA candidates are often differentially expressed in failing hearts, with an inverse correlation between 3'UTR length and the level of gene expression. Protein levels of the APA regulator, poly(A)-binding protein nuclear-1 were substantially downregulated in failing hearts.
We provide genome-wide, high-resolution polyadenylation maps of the human heart and show that the 3'end formation of mRNA is dynamic in heart failure, suggesting that APA-mediated 3'UTR length modulation represents an additional layer of gene regulation in failing hearts.
mRNA 的交替剪接和多聚腺苷酸化（APA）代表了一层基因调控，迄今为止，这在心脏中尚未得到探索。这一现象可能很重要，因为 mRNA 中 poly(A) 尾巴的位置影响 3'非翻译区（UTR）的长度，而 3'UTR 的长度是基因表达的关键决定因素。
研究人类心脏中 3'UTR 的长度是否受 APA 调控，以及在衰竭心脏中是否会发生变化。
我们使用 3'末端 RNA 测序（e3'-Seq）直接测量健康和衰竭人类心脏标本中 APA 的全局模式。通过监测这些心脏中的多聚腺苷酸化谱，我们在许多基因中确定了特定于疾病的 APA 特征。有趣的是，心力衰竭中 3'UTR 缩短的许多基因富含 RNA 结合等功能群，而 3'UTR 较长的基因富含细胞骨架组织和肌动蛋白结合。在更大系列的人类心脏中进行的 RNA 测序表明，这些 APA 候选物在衰竭心脏中通常表达不同，3'UTR 长度与基因表达水平呈负相关。衰竭心脏中 APA 调节因子多聚（A）结合蛋白核-1 的蛋白水平显著下调。
我们提供了人类心脏的全基因组、高分辨率多聚腺苷酸化图谱，并表明在心力衰竭中 mRNA 的 3'末端形成是动态的，这表明 APA 介导的 3'UTR 长度调节代表了衰竭心脏中基因调控的另一层。
