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; Lili Zhang

doi:10.1038/s41467-023-38002-w

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^*, Lili Zhang^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Article number	2390
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-38002-w
State	Published - Dec 2023

Funding

This work is supported by grants from NIH/NIGMS (R01GM125632 and R01GM138407 to K.C.) and NIH/NHLBI (R01HL133254 to J.C. and K.C.; R01HL148338 to J.C. and K.C.; 1R01HL132155 to L.F.; and R01HL155632 to L.Z.), and Additional Ventures (Single Ventricle Research Foundation to L.Z.), George and Angelina foundation to L.F., and Cancer Prevention Research Institute of Texas (CPRIT) grants RP150611 and RP170002. Q.C. is supported by U.S. Department of Defense (W81XWH-15-1-0639 and W81XWH-17-1-0357), American Cancer Society (TBE-128382) and NIH/NCI (R01CA208257).

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Epigenetic landscape reveals MECOM as an endothelial lineage regulator",

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.",

author = "Jie Lv and Shu Meng and Qilin Gu and Rongbin Zheng and Xinlei Gao and Kim, {Jun dae} and Min Chen and Bo Xia and Yihan Zuo and Sen Zhu and Dongyu Zhao and Yanqiang Li and Guangyu Wang and Xin Wang and Qingshu Meng and Qi Cao and Cooke, {John P.} and Longhou Fang and Kaifu Chen and Lili Zhang",

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doi = "10.1038/s41467-023-38002-w",

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AU - Lv, Jie

AU - Meng, Shu

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AU - Gao, Xinlei

AU - Kim, Jun dae

AU - Chen, Min

AU - Xia, Bo

AU - Zuo, Yihan

AU - Zhu, Sen

AU - Zhao, Dongyu

AU - Li, Yanqiang

AU - Wang, Guangyu

AU - Wang, Xin

AU - Meng, Qingshu

AU - Cao, Qi

AU - Cooke, John P.

AU - Fang, Longhou

AU - Chen, Kaifu

AU - Zhang, Lili

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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Epigenetic landscape reveals MECOM as an endothelial lineage regulator

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UN SDGs

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