Dynamically and epigenetically coordinated GATA/ETS/SOX transcription factor expression is indispensable for endothelial cell differentiation.
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.
Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan.|Division of Vascular Biology, RCAST, The University of Tokyo, Tokyo 153-8904, Japan.|Division of Systems Biology, RCAST, The University of Tokyo, Tokyo 153-8904, Japan.
Yasuharu
Y
Kanki
Division of Genome Sciences, RCAST, The University of Tokyo, Tokyo 153-8904, Japan.
Ryo
R
Nakaki
Department of Systems Biology, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan.
Teppei
T
Shimamura
Department of Stem Cell Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.|Deparment of Cell Growth and Differentiation, CiRA, Kyoto University, Kyoto 606-8507, Japan.
Taichi
T
Matsunaga
Department of Stem Cell Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.|Deparment of Cell Growth and Differentiation, CiRA, Kyoto University, Kyoto 606-8507, Japan.
Kohei
K
Yamamizu
Department of Stem Cell Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.|Deparment of Cell Growth and Differentiation, CiRA, Kyoto University, Kyoto 606-8507, Japan.
Shiori
S
Katayama
Division of Vascular Biology, RCAST, The University of Tokyo, Tokyo 153-8904, Japan.|Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo 181-8611, Japan.
Jun-Ichi
JI
Suehiro
Division of Vascular Biology, RCAST, The University of Tokyo, Tokyo 153-8904, Japan.|Division of Systems Biology, RCAST, The University of Tokyo, Tokyo 153-8904, Japan.
Tsuyoshi
T
Osawa
Division of Genome Sciences, RCAST, The University of Tokyo, Tokyo 153-8904, Japan.
Hiroyuki
H
Aburatani
Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan.|Division of Systems Biology, RCAST, The University of Tokyo, Tokyo 153-8904, Japan.
Tatsuhiko
T
Kodama
Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan.
Youichiro
Y
Wada
Department of Stem Cell Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.|Deparment of Cell Growth and Differentiation, CiRA, Kyoto University, Kyoto 606-8507, Japan.
Jun K
JK
Yamashita
Division of Vascular Biology, RCAST, The University of Tokyo, Tokyo 153-8904, Japan.|Division of Molecular and Vascular Biology, IRDA, Kumamoto University, Kumamoto 860-0811, Japan.
Takashi
T
Minami
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D044127:Epigenesis, Genetic; D050989:GATA2 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D055760:SOXF Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C503994:ER71 protein, mouse; C494042:Ets1 protein, mouse; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D006657:Histones; D020033:Protein Isoforms; D050784:Proto-Oncogene Protein c-ets-1; D034741:RNA, Small Interfering; D055760:SOXF Transcription Factors; C102515:Sox7 protein, mouse; D014157:Transcription Factors