Li Xing, Martinez-Fernandez Almudena, Hartjes Katherine A, Kocher Jean-Pierre A, Olson Timothy M, Terzic Andre, Nelson Timothy J
Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota;
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota;
Physiol Genomics. 2014 Jul 1;46(13):482-95. doi: 10.1152/physiolgenomics.00015.2014. Epub 2014 May 6.
Mammalian heart development is built on highly conserved molecular mechanisms with polygenetic perturbations resulting in a spectrum of congenital heart diseases (CHD). However, knowledge of cardiogenic ontogeny that regulates proper cardiogenesis remains largely based on candidate-gene approaches. Mapping the dynamic transcriptional landscape of cardiogenesis from a genomic perspective is essential to integrate the knowledge of heart development into translational applications that accelerate disease discovery efforts toward mechanistic-based treatment strategies. Herein, we designed a time-course transcriptome analysis to investigate the genome-wide dynamic expression landscape of innate murine cardiogenesis ranging from embryonic stem cells to adult cardiac structures. This comprehensive analysis generated temporal and spatial expression profiles, revealed stage-specific gene functions, and mapped the dynamic transcriptome of cardiogenesis to curated pathways. Reconciling known genetic underpinnings of CHD, we deconstructed a disease-centric dynamic interactome encoded within this cardiogenic atlas to identify stage-specific developmental disturbances clustered on regulation of epithelial-to-mesenchymal transition (EMT), BMP signaling, NF-AT signaling, TGFb-dependent EMT, and Notch signaling. Collectively, this cardiogenic transcriptional landscape defines the time-dependent expression of cardiac ontogeny and prioritizes regulatory networks at the interface between health and disease.
哺乳动物心脏发育建立在高度保守的分子机制之上，多基因扰动会导致一系列先天性心脏病（CHD）。然而，调节正常心脏发生的心脏发生个体发育学知识在很大程度上仍基于候选基因方法。从基因组角度绘制心脏发生的动态转录图谱，对于将心脏发育知识整合到转化应用中至关重要，这些应用可加速针对基于机制的治疗策略的疾病发现工作。在此，我们设计了一项时间进程转录组分析，以研究从胚胎干细胞到成年心脏结构的先天性小鼠心脏发生的全基因组动态表达图谱。这项全面分析生成了时空表达谱，揭示了阶段特异性基因功能，并将心脏发生的动态转录组映射到经过整理的通路。结合CHD已知的遗传基础，我们解构了这个心脏发生图谱中编码的以疾病为中心的动态相互作用组，以识别聚集在上皮-间充质转化（EMT）、BMP信号传导、NF-AT信号传导、TGFb依赖性EMT和Notch信号传导调节上的阶段特异性发育障碍。总体而言，这种心脏发生转录图谱定义了心脏个体发育的时间依赖性表达，并确定了健康与疾病界面处的调控网络的优先级。
