Dynamic gene expression patterns in animal models of early and late heart failure reveal biphasic-bidirectional transcriptional activation of signaling pathways.
Dynamic gene expression patterns in animal models of early and late heart failure reveal biphasic-bidirectional transcriptional activation of signaling pathways.
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DOI：
10.1152/physiolgenomics.00054.2014
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发表时间：
2014-10
影响因子：
4.6
通讯作者：
J. Rowell;N. Koitabashi;D. Kass;Andreas S Barth
中科院分区：
文献类型：
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作者：
J. Rowell;N. Koitabashi;D. Kass;Andreas S Barth
心力衰竭（HF）中心脏基因表达的改变主要是通过终末期疾病的单点分析来确定的。这可能会错过基因表达的早期变化，这些变化是短暂的和/或方向与后来观察到的相反。来自最大的微阵列数据存储库（基因表达Omnibus）的心肌数据集产生了六项具有时间过程数据的心衰研究。检测了正常对照组、早期HF（2周）之间差异表达的转录本，并分析了KEGG通路和预测的调节控制元件。我们发现基因表达遵循不同的模式：代谢途径的下调发生在早期，并持续到晚期HF。相比之下，大多数信号通路经历复杂的双相模式：钙信号、p53、凋亡和MAPK通路表现出双向反应，早期下降，晚期上升。这些特征与特定的microRNA （miRNA）和转录调节因子相兼容：雌激素相关受体-α和肌细胞增强因子-2结合位点在下调转录物的启动子区域中被过度代表。同时，E2f和ETS家族成员（e- 26，包括Gabp、Elf1和Ets2）、血清应答和干扰素调节因子在双相双向和晚上调转录本中的结合位点过多。HF下调的mirna结合位点在上调的转录本中更为常见（例如，HF早期的miRNA-22、-133a/b和-150，HF晚期的miRNA-1、-9、-499）。在HF的发展过程中，基因表达的特点是由特定的相互关联的调节机制控制的转录物动态重叠。虽然代谢基因类别在HF中表现出早期和持续的下调，但信号通路经历一个复杂的双相模式，早期下调和更明显的晚期上调。
Altered cardiac gene expression in heart failure (HF) has mostly been identified by single-point analysis of end-stage disease. This may miss earlier changes in gene expression that are transient and/or directionally opposite to those observed later. Myocardial datasets from the largest microarray data repository (Gene Expression Omnibus) yielded six HF studies with time-course data. Differentially expressed transcripts between nonfailing controls, early HF (2 wk) were determined, and analysis of KEGG pathways and predicted regulatory control elements performed. We found that gene expression followed varying patterns: Downregulation of metabolic pathways occurred early and was sustained into late-stage HF. In contrast, most signaling pathways undergo a complex biphasic pattern: Calcium signaling, p53, apoptosis, and MAPK pathways displayed a bidirectional response, declining early but rising late. These profiles were compatible with specific microRNA (miRNA) and transcription regulators: Estrogen-related receptor-α and myocyte-enhancer factor-2 binding sites were overrepresented in the promoter regions of downregulated transcripts. Concurrently, there were overrepresented binding sites for E2f and ETS family members (E-Twenty Six, including Gabp, Elf1, and Ets2), serum response and interferon regulated factor in biphasic-bidirectional and late-upregulated transcripts. Binding sites for miRNAs downregulated by HF were more common in upregulated transcripts (e.g., miRNA-22,-133a/b, and -150 in early HF and miRNA-1,-9,-499 in late HF). During the development of HF, gene expression is characterized by dynamic overlapping sets of transcripts controlled by specific interrelated regulatory mechanisms. While metabolic gene classes show early and sustained downregulation in HF, signaling pathways undergo a complex biphasic pattern with early down- and more pronounced late upregulation.