title: Induction of hematopoietic and endothelial cell program orchestrated by ETS transcription factor ER71/ETV2.
abstract: The ETS factor ETV2 (aka ER71) is essential for the generation of the blood and vascular system, as ETV2 deficiency leads to a complete block in blood and endothelial cell formation and embryonic lethality in the mouse. However, the ETV2-mediated gene regulatory network and signaling governing hematopoietic and endothelial cell development are poorly understood. Here, we map ETV2 global binding sites and carry out in vitro differentiation of embryonic stem cells, and germ line and conditional knockout mouse studies to uncover mechanisms involved in the hemangiogenic fate commitment from mesoderm. We show that ETV2 binds to enhancers that specify hematopoietic and endothelial cell lineages. We find that the hemangiogenic progenitor population in the developing embryo can be identified as FLK1(high)PDGFRα(-). Notably, these hemangiogenic progenitors are exclusively sensitive to ETV2-dependent FLK1 signaling. Importantly, ETV2 turns on other Ets genes, thereby establishing an ETS hierarchy. Consequently, the hematopoietic and endothelial cell program initiated by ETV2 is maintained partly by other ETS factors through an ETS switching mechanism. These findings highlight the critical role that transient ETV2 expression plays in the regulation of hematopoietic and endothelial cell lineage specification and stability.
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Fang
authors: F
authors: Liu
authors: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Daofeng
authors: D
authors: Li
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Yik Yeung Lawrence
authors: YY
authors: Yu
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Inyoung
authors: I
authors: Kang
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Min-Ji
authors: MJ
authors: Cha
authors: Department of Pediatrics, Children's Heart Research and Outcomes Center, Emory University School of Medicine, Atlanta, GA, USA.
authors: Ju Young
authors: JY
authors: Kim
authors: Department of Pediatrics, Children's Heart Research and Outcomes Center, Emory University School of Medicine, Atlanta, GA, USA.
authors: Changwon
authors: C
authors: Park
authors: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors: Dennis K
authors: DK
authors: Watson
authors: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA twang@genetics.wustl.edu kchoi@wustl.edu.
authors: Ting
authors: T
authors: Wang
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA Developmental, Regenerative, and Stem Cell Biology Program, Washington University School of Medicine, St. Louis, MO, USA twang@genetics.wustl.edu kchoi@wustl.edu.
authors: Kyunghee
authors: K
authors: Choi
mesh_terms: D000818:Animals; D001665:Binding Sites; D001773:Blood Cells / Q000166:cytology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D059372:Nucleotide Motifs; D009928:Organ Specificity / Q000235:genetics; D056510:Position-Specific Scoring Matrices; D011485:Protein Binding; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism
chemical_list: C503994:ER71 protein, mouse; D014157:Transcription Factors; D042442:Vascular Endothelial Growth Factors; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: ChIP‐Seq; ER71/ETV2; ETS hierarchy; ETS switching; VEGFR2/FLK1; hemangioblast