Epigenetic delineation of the earliest cardiac lineage segregation by single-cell multi-omics

Author:

Xie Peng12ORCID,Jiang Xu3,He Jingjing3,Pan Qingyun3,Yang Xianfa4ORCID,Zheng Yanying3,Fan Wenli4,Wu Chen1,Zheng Weiheng1,Fang Ke3,Si Shuhan3,Zhu Shiqi3,Yang Yi3,Zhong Tao P5ORCID,Yang Zhongzhou4,Wei Ke6,Xie Wei23ORCID,Jing Naihe78ORCID,Luo Zhuojuan23,Lin Chengqi23ORCID

Affiliation:

1. Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, School of Biological Science and Medical Engineering, Southeast University

2. Co-innovation Center of Neuroregeneration, Nantong University

3. Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University

4. State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University

5. Shanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, School of Life Sciences, East China Normal University

6. Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Department of Molecular and Cellular Biology, Tongji University

7. Guangzhou Laboratory

8. CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences

Abstract

The mammalian heart is formed from multiple mesoderm-derived cell lineages. However, it remains largely unknown when and how the specification of mesoderm towards cardiac lineages is determined. Here, we systematically depict the transcriptional trajectories toward cardiomyocyte in early mouse embryo, and characterize the epigenetic landscapes underlying the early mesodermal lineage specification by single-cell multi-omics analyses. The analyses also reveal distinct core regulatory networks (CRN) in controlling specification of mesodermal lineages. We further demonstrate the essential role HAND1 and FOXF1 in driving the earliest cardiac progenitors specification. These key transcription factors occupy at distinct enhancers, but function synergistically and hierarchically to regulate the expression of cardiac-specific genes. In addition, HAND1 is required for exiting from the nascent mesoderm program, while FOXF1 is essential for driving cardiac differentiation during MJH specification. Our findings establish transcriptional and epigenetic determinants specifying the early cardiac lineage, providing insights for the investigation of congenital heart defects.

Publisher

eLife Sciences Publications, Ltd

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