Molecular Signatures and Networks of Cardiomyocyte Differentiation in Humans and Mice

Yumei Wang; Na Yi; Yi Hu; Xianxiao Zhou; Hanyu Jiang; Qin Lin; Rou Chen; Huan Liu; Yanqiong Gu; Chang Tong; Min Lu; Junfang Zhang; Bin Zhang; Luying Peng; Li Li

doi:10.1016/j.omtn.2020.07.011

Molecular Signatures and Networks of Cardiomyocyte Differentiation in Humans and Mice

Mol Ther Nucleic Acids. 2020 Sep 4:21:696-711. doi: 10.1016/j.omtn.2020.07.011. Epub 2020 Jul 10.

Authors

Yumei Wang¹, Na Yi¹, Yi Hu¹, Xianxiao Zhou², Hanyu Jiang³, Qin Lin¹, Rou Chen³, Huan Liu¹, Yanqiong Gu³, Chang Tong³, Min Lu³, Junfang Zhang⁴, Bin Zhang², Luying Peng⁵, Li Li⁶

Affiliations

¹ 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.
² 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.
³ Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
⁴ Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Department of Medical Genetics, Tongji University School of Medicine, Shanghai 200092, China.
⁵ 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. Electronic address: luyingpeng@tongji.edu.cn.
⁶ 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. Electronic address: lilirz@tongji.edu.cn.

Abstract

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.

Keywords: cardiomyocyte differentiation; differentially expressed gene; embryonic stem cell; gene co-expression network; module; transcription factor.