Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.
Department of Biomedicine, University of Basel, Basel, Switzerland.
Sci Rep. 2018 Oct 17;8(1):15312. doi: 10.1038/s41598-018-33478-9.
Comparative genomic studies in primates have the potential to reveal the genetic and mechanistic basis for human specific traits. These studies may also help us better understand inter-species phenotypic differences that are clinically relevant. Unfortunately, the obvious limitation on sample collection and experimentation in humans and non-human apes severely restrict our ability to perform dynamic comparative studies in primates. Induced pluripotent stem cells (iPSCs), and their corresponding differentiated cells, may provide a suitable alternative system for dynamic comparative studies. Yet, to effectively use iPSCs and differentiated cells for comparative studies, one must characterize the extent to which these systems faithfully represent biological processes in primary tissues. To do so, we compared gene expression data from primary adult heart tissue and iPSC-derived cardiomyocytes from multiple human and chimpanzee individuals. We determined that gene expression in cultured cardiomyocytes from both human and chimpanzee is most similar to that of adult hearts compared to other adult tissues. Using a comparative framework, we found that 50% of gene regulatory differences between human and chimpanzee hearts are also observed between species in cultured cardiomyocytes; conversely, inter-species regulatory differences seen in cardiomyocytes are found significantly more often in hearts than in other primary tissues. Our work provides a detailed description of the utility and limitation of differentiated cardiomyocytes as a system for comparative functional genomic studies in primates.
灵长类动物的比较基因组研究有可能揭示人类特有特征的遗传和机制基础。这些研究也可能帮助我们更好地理解具有临床相关性的种间表型差异。不幸的是，人类和非人类猿类样本采集和实验的明显限制严重限制了我们在灵长类动物中进行动态比较研究的能力。诱导多能干细胞（iPSCs）及其相应的分化细胞，可能为动态比较研究提供合适的替代系统。然而，要有效地将 iPSCs 和分化细胞用于比较研究，就必须描述这些系统在多大程度上真实地代表了原代组织中的生物学过程。为此，我们比较了来自多个人类和黑猩猩个体的原代成人心肌组织和 iPSC 衍生的心肌细胞的基因表达数据。我们确定，与其他成年组织相比，培养的来自人类和黑猩猩的心肌细胞中的基因表达与成年心脏最为相似。通过比较框架，我们发现，人类和黑猩猩心脏之间 50%的基因调控差异也存在于培养的心肌细胞中；相反，在心肌细胞中观察到的种间调控差异在心脏中比在其他原代组织中更为常见。我们的工作详细描述了分化的心肌细胞作为灵长类动物比较功能基因组研究系统的实用性和局限性。
