Dynamic Gene Regulatory Networks Drive Hematopoietic Specification and Differentiation

Highlights•Comprehensive genome-scale resource for studying embryonic blood cell specification•Genome-scale definition of cis elements driving differential gene expression•A gene regulatory network model for hematopoiesis aiding reprogramming experiments•Analysis suggests a role for TEAD factors in hematopoietic specificationSummaryMetazoan 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.Graphical abstract