Abstract
SummaryMetazoan development involves the successive activation and silencing of specific gene expression programs and is driven by tissue-specific transcription factors programming the chromatin landscape. To understand how this process executes an entire developmental pathway, we generated global gene expression, chromatin accessibility, histone modification, and transcription factor binding data from purified embryonic stem cell-derived cells representing six sequential stages of hematopoietic specification and differentiation. Our data reveal the nature of regulatory elements driving differential gene expression and inform how transcription factor binding impacts on promoter activity. We present a dynamic core regulatory network model for hematopoietic specification and demonstrate its utility for the design of reprogramming experiments. Functional studies motivated by our genome-wide data uncovered a stage-specific role for TEAD/YAP factors in mammalian hematopoietic specification. Our study presents a powerful resource for studying hematopoiesis and demonstrates how such data advance our understanding of mammalian development.
Highlights
Cellular identities in multicellular organisms are defined by their individual gene expression programs and are established in a series of cell fate changes starting from pluripotent cells of the embryo
Capturing a Complete Developmental Pathway using Genome-Scale Technologies To study the specification of hematopoietic cells and their further differentiation, we employed mouse embryonic stem cells (ESCs) in vitro differentiation to purify well-defined intermediate cell populations en route from pluripotent ESCs to adherent macrophages (Lancrin et al, 2009; Sroczynska et al, 2009), making use of a Brachyury GFP reporter (Fehling et al, 2003) and surface marker expression
Pluripotent ESCs differentiate to mesoderm (MES) cells (Bry:GFP+/Flk1À), which progress to the hemangioblast (HB) stage (Bry:GFP+/ Flk1+) with smooth muscle, endothelial, and hematopoietic potential, followed by the hemogenic endothelium (HE) stage that has both endothelial and hematopoietic potential (CD41À/Tie2+/ Kit+)
Summary
Cellular identities in multicellular organisms are defined by their individual gene expression programs and are established in a series of cell fate changes starting from pluripotent cells of the embryo. Studies of chromatin programming and gene expression during the generation of mature blood cells from hematopoietic stem cells were instrumental in defining the concept that development at the level of chromatin is a gradual and hierarchical process starting long before the overt transcriptional activation of lineage-specific genes (Bonifer et al, 2008; Hoogenkamp et al, 2009; Org et al, 2015; Wamstad et al, 2012; Wang et al, 2015) This notion is illustrated by the regulatory circuit essential for macrophage differentiation, the gene encoding TF PU. (Spi1), and its target, the Csf1r growth factor receptor gene (reviewed in Bonifer et al, 2008). We know very little about how such transcriptional control mechanisms are interlinked with outside signaling
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