Epigenetic landscape reveals MECOM as an endothelial lineage regulator

Jie Lv, Shu Meng, Qilin Gu, Rongbin Zheng, Xinlei Gao, Jun-dae Kim, Min Chen, Bo Xia, Yihan Zuo, Sen Zhu, Dongyu Zhao, Yanqiang Li, Guangyu Wang, Xin Wang, Qingshu Meng, Qi Cao, John P. Cooke (), Longhou Fang (), Kaifu Chen () and Lili Zhang ()
Additional contact information
Jie Lv: Houston Methodist Research Institute
Shu Meng: Houston Methodist Research Institute
Qilin Gu: Houston Methodist Research Institute
Rongbin Zheng: Boston Children’s Hospital
Xinlei Gao: Houston Methodist Research Institute
Jun-dae Kim: Houston Methodist Research Institute
Min Chen: Boston Children’s Hospital
Bo Xia: Houston Methodist Research Institute
Yihan Zuo: Boston Children’s Hospital
Sen Zhu: Houston Methodist Research Institute
Dongyu Zhao: Houston Methodist Research Institute
Yanqiang Li: Houston Methodist Research Institute
Guangyu Wang: Houston Methodist Research Institute
Xin Wang: Houston Methodist Research Institute
Qingshu Meng: Northwestern University Feinberg School of Medicine
Qi Cao: Northwestern University Feinberg School of Medicine
John P. Cooke: Houston Methodist Research Institute
Longhou Fang: Houston Methodist Research Institute
Kaifu Chen: Houston Methodist Research Institute
Lili Zhang: Houston Methodist Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract A comprehensive understanding of endothelial cell lineage specification will advance cardiovascular regenerative medicine. Recent studies found that unique epigenetic signatures preferentially regulate cell identity genes. We thus systematically investigate the epigenetic landscape of endothelial cell lineage and identify MECOM to be the leading candidate as an endothelial cell lineage regulator. Single-cell RNA-Seq analysis verifies that MECOM-positive cells are exclusively enriched in the cell cluster of bona fide endothelial cells derived from induced pluripotent stem cells. Our experiments demonstrate that MECOM depletion impairs human endothelial cell differentiation, functions, and Zebrafish angiogenesis. Through integrative analysis of Hi-C, DNase-Seq, ChIP-Seq, and RNA-Seq data, we find MECOM binds enhancers that form chromatin loops to regulate endothelial cell identity genes. Further, we identify and verify the VEGF signaling pathway to be a key target of MECOM. Our work provides important insights into epigenetic regulation of cell identity and uncovered MECOM as an endothelial cell lineage regulator.

Date: 2023
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DOI: 10.1038/s41467-023-38002-w

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