Wang Yumei, Yi Na, Hu Yi, Zhou Xianxiao, Jiang Hanyu, Lin Qin, Chen Rou, Liu Huan, Gu Yanqiong, Tong Chang, Lu Min, Zhang Junfang, Zhang Bin, Peng Luying, Li Li
Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Institute of Medical Genetics, Tongji University, Shanghai 200092, China; Department of Medical Genetics, Tongji University School of Medicine, Shanghai 200092, China; Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Research Units of Origin and Regulation of Heart Rhythm, Chinese Academy of Medical Sciences, Shanghai 200092, China.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Mol Ther Nucleic Acids. 2020 Sep 4;21:696-711. doi: 10.1016/j.omtn.2020.07.011. Epub 2020 Jul 10.
Cardiomyocyte differentiation derived from embryonic stem cells (ESCs) is a complex process involving molecular regulation of multiple levels. In this study, we first identify and compare differentially expressed gene (DEG) signatures of ESC-derived cardiomyocyte differentiation (ESCDCD) in humans and mice. Then, the multiscale embedded gene co-expression network analysis (MEGENA) of the human ESCDCD dataset is performed to identify 212 significantly co-expressed gene modules, which capture well the regulatory information of cardiomyocyte differentiation. Three modules respectively involved in the regulation of stem cell pluripotency, Wnt, and calcium pathways are enriched in the DEG signatures of the differentiation phase transition in the two species. Three human-specific cardiomyocyte differentiation phase transition modules are identified. Moreover, the potential regulation mechanisms of transcription factors during cardiomyocyte differentiation are also illustrated. Finally, several novel key drivers of ESCDCD are identified with the evidence of their expression during mouse embryonic cardiomyocyte differentiation. Using an integrative network analysis, the core molecular signatures and gene subnetworks (modules) underlying cardiomyocyte lineage commitment are identified in both humans and mice. Our findings provide a global picture of gene-gene co-regulation and identify key regulators during ESCDCD.
源自胚胎干细胞（ESC）的心肌细胞分化是一个涉及多个层面分子调控的复杂过程。在本研究中，我们首先鉴定并比较了人类和小鼠ESC来源的心肌细胞分化（ESCDCD）中差异表达基因（DEG）特征。然后，对人类ESCDCD数据集进行多尺度嵌入式基因共表达网络分析（MEGENA），以识别212个显著共表达的基因模块，这些模块很好地捕捉了心肌细胞分化的调控信息。分别参与干细胞多能性、Wnt和钙途径调控的三个模块在两个物种分化阶段转变的DEG特征中富集。鉴定出三个人类特有的心肌细胞分化阶段转变模块。此外，还阐述了心肌细胞分化过程中转录因子的潜在调控机制。最后，通过在小鼠胚胎心肌细胞分化过程中的表达证据，鉴定出几个ESCDCD的新型关键驱动因子。通过整合网络分析，在人类和小鼠中均鉴定出了心肌细胞谱系定向分化的核心分子特征和基因子网（模块）。我们的研究结果提供了基因-基因共调控的全局图景，并鉴定了ESCDCD过程中的关键调节因子。
