Phenotypic screen quantifying differential regulation of cardiac myocyte hypertrophy identifies CITED4 regulation of myocyte elongation.
Phenotypic screen quantifying differential regulation of cardiac myocyte hypertrophy identifies CITED4 regulation of myocyte elongation.
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DOI：
10.1016/j.yjmcc.2014.02.013
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发表时间：
2014-07
影响因子：
5
通讯作者：
Saucerman, Jeffrey J.
中科院分区：
文献类型：
--
作者：
Ryall, Karen A.;Bezzerides, Vassilios J.;Rosenzweig, Anthony;Saucerman, Jeffrey J.
心脏肥大是由一个高度连接的信号网络控制的，该网络具有许多心肌细胞大小的效应器。需要量化单个通路对形状和转录丰度的特定变化的贡献，以更好地理解肥大信号传导并改善心力衰竭治疗。我们用15种肥大激动剂刺激心肌细胞，并使用高通量显微镜和qPCR定量表征5种形状特征的差异调节和12种基因的转录水平。所测量的转录本与表型相关，包括纤维化、细胞死亡、收缩性、增殖、血管生成、炎症和胎儿心脏基因程序。虽然肥大途径是高度相关的，激动剂筛选揭示了15种受体激动剂的不同肥大表型特征。然后，我们使用输入和输出的k-means聚类来识别连接输入模块和输出模块的网络映射。在输入和输出中识别出五个模块，其中许多适应不良的输出组合在一个模块中：Bax、C/EBPβ、Serca 2a、TNFα和CTGF。随后，我们确定了激动剂筛选中揭示的两种相关性的机制：AngII引起的纤维化和细胞死亡信号（CTGF和Bax mRNA）调节因子之间的相关性; Nrg 1引起的肌细胞增殖（CITED 4 mRNA）和延长。后续实验显示CTGF对Bax mRNA水平的正向调节以及连接Nrg 1、CITED 4和延伸的不连贯前馈环。通过这种激动剂筛选，我们确定了心脏肥大信号网络中最具影响力的输入，这些输入具有与病理性和保护性肥大信号相关的各种特征，并在心肌细胞表型中共享调节。
Cardiac hypertrophy is controlled by a highly connected signaling network with many effectors of cardiac myocyte size. Quantification of the contribution of individual pathways to specific changes in shape and transcript abundance is needed to better understand hypertrophy signaling and to improve heart failure therapies. We stimulated cardiac myocytes with 15 hypertrophic agonists and quantitatively characterized differential regulation of 5 shape features using high-throughput microscopy and transcript levels of 12 genes using qPCR. Transcripts measured were associated with phenotypes including fibrosis, cell death, contractility, proliferation, angiogenesis, inflammation, and the fetal cardiac gene program. While hypertrophy pathways are highly connected, the agonist screen revealed distinct hypertrophy phenotypic signatures for the 15 receptor agonists. We then used k-means clustering of inputs and outputs to identify a network map linking input modules to output modules. Five modules were identified within inputs and outputs with many maladaptive outputs grouping together in one module: Bax, C/EBPβ, Serca2a, TNFα, and CTGF. Subsequently, we identified mechanisms underlying two correlations revealed in the agonist screen: correlation between regulators of fibrosis and cell death signaling (CTGF and Bax mRNA) caused by AngII; and myocyte proliferation (CITED4 mRNA) and elongation caused by Nrg1. Follow-up experiments revealed positive regulation of Bax mRNA level by CTGF and an incoherent feedforward loop linking Nrg1, CITED4 and elongation. With this agonist screen, we identified the most influential inputs in the cardiac hypertrophy signaling network for a variety of features related to pathological and protective hypertrophy signaling and shared regulation among cardiac myocyte phenotypes.
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影响因子：
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通讯作者：
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通讯作者：
Hill JA
影响因子：
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Boström P;Mann N;Wu J;Quintero PA;Plovie ER;Panáková D;Gupta RK;Xiao C;MacRae CA;Rosenzweig A;Spiegelman BM
通讯作者：
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