Journal
NUCLEIC ACIDS RESEARCH
Volume 45, Issue 8, Pages 4344-4358Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkx159
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Funding
- Japan Society for the Promotion of Science [24710227, 15H01348]
- NOVARTIS Foundation (Japan) for the Promotion of Science
- Uehara Memorial Foundation
- Cooperative Research Program of the Institute for Frontier Medical Sciences, Kyoto University, Japan
- Leading-edge Research Promotion Fund from Japan Society for the Promotion of Science [LS038]
- Life Science promotion Fund (Daiichi-Sankyo)
- Grants-in-Aid for Scientific Research [26290035, 15K12139, 16K15438, 17H03580, 16H06279, 15H01348, 26250041, 24710227, 15KK0251, 26710013, 17H03614] Funding Source: KAKEN
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Although studies of the differentiation from mouse embryonic stem (ES) cells to vascular endothelial cells (ECs) provide an excellent model for investigating the molecular mechanisms underlying vascular development, temporal dynamics of gene expression and chromatin modifications have not been well studied. Herein, using transcriptomic and epigenomic analyses based on H3K4me3 and H3K27me3 modifications at a genome-wide scale, we analysed the EC differentiation steps from ES cells and crucial epigenetic modifications unique to ECs. We determined that Gata2, Fli1, Sox7 and Sox18 are master regulators of EC that are induced following expression of the haemangioblast commitment pioneer factor, Etv2. These master regulator gene loci were repressed by H3K27me3 throughout the mesoderm period but rapidly transitioned to histone modification switching from H3K27me3 to H3K4me3 after treatment with vascular endothelial growth factor. SiRNA knockdown experiments indicated that these regulators are indispensable not only for proper EC differentiation but also for blocking the commitment to other closely aligned lineages. Collectively, our detailed epigenetic analysis may provide an advanced model for understanding temporal regulation of chromatin signatures and resulting gene expression profiles during EC commitment. These studies may inform the future development of methods to stimulate the vascular endothelium for regenerative medicine.
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