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    Dynamically and epigenetically coordinated GATA/ETS/SOX transcription factor expression is indispensable for endothelial cell differentiation.
    Nucleic Acids Res 2017 May;45(8):4344-4358
    Division of Vascular Biology, RCAST, The University of Tokyo, Tokyo 153-8904, Japan.
    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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    Etv2/ER71 induces vascular mesoderm from Flk1+PDGFRα+ primitive mesoderm.
    Blood 2011 Dec 12;118(26):6975-86. Epub 2011 Sep 12.
    Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan.
    Etv2 (Ets Variant 2) has been shown to be an indispensable gene for the development of hematopoietic cells (HPCs)/endothelial cells (ECs). However, how Etv2 specifies the mesoderm-generating HPCs/ECs remains incompletely understood. In embryonic stem cell (ESC) differentiation culture and Etv2-null embryos, we show that Etv2 is dispensable for generating primitive Flk-1(+)/PDGFRα(+) mesoderm but is required for the progression of Flk-1(+)/PDGFRα(+) cells into vascular/hematopoietic mesoderm. Read More
    Profiling of transcriptional and epigenetic changes during directed endothelial differentiation of human embryonic stem cells identifies FOXA2 as a marker of early mesoderm commitment.
    Stem Cell Res Ther 2013 Apr 24;4(2):36. Epub 2013 Apr 24.
    Introduction: Differentiation of vascular endothelial cells (ECs) in clinically relevant numbers for injection into ischaemic areas could offer therapeutic potential in the treatment of cardiovascular conditions, including myocardial infarction, peripheral vascular disease and stroke. While we and others have demonstrated successful generation of functional endothelial-like cells from human embryonic stem cells (hESCs), little is understood regarding the complex transcriptional and epigenetic changes that occur during differentiation, in particular during early commitment to a mesodermal lineage.

    Methods: We performed the first gene expression microarray study of hESCs undergoing directed differentiation to ECs using a monolayer-based, feeder-free and serum-free protocol. Read More
    Dynamic regulation of epigenomic landscapes during hematopoiesis.
    BMC Genomics 2013 Mar 19;14:193. Epub 2013 Mar 19.
    Systems Biology Center, NHLBI, NIH, Rockville Pike, Bethesda, MD, USA.
    Background: Human blood develops from self-renewing hematopoietic stem cells to terminal lineages and necessitates regulator and effector gene expression changes; each cell type specifically expresses a subset of genes to carry out a specific function. Gene expression changes coincide with histone modification, histone variant deposition, and recruitment of transcription-related enzymes to specific genetic loci. Transcriptional regulation has been mostly studied using in vitro systems while epigenetic changes occurring during in vivo development remain poorly understood. Read More
    Induction of hematopoietic and endothelial cell program orchestrated by ETS transcription factor ER71/ETV2.
    EMBO Rep 2015 May 23;16(5):654-69. Epub 2015 Mar 23.
    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
    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. Read More