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Precise control of developmental processes is encoded in the genome in
the form of gene regulatory networks (GRNs). Such multi-factorial
systems are difficult to decode in vertebrates owing to their complex
gene hierarchies and dynamic molecular interactions. Here we present a
genome-wide in vivo reconstruction of the GRN underlying
development of the multipotent neural crest (NC) embryonic cell
population. By coupling NC-specific epigenomic and transcriptional
profiling at population and single-cell levels with genome/epigenome
engineering in vivo, we identify multiple regulatory layers
governing NC ontogeny, including NC-specific enhancers and
super-enhancers, novel trans-factors and cis-signatures allowing to
reverse engineer the NC-GRN at unprecedented resolution. Furthermore,
identification and dissection of divergent upstream combinatorial
regulatory codes has afforded new insights into opposing gene circuits
that define canonical and neural NC fates early during NC ontogeny. Our
integrated approach, allowing dissection of cell-type-specific
regulatory circuits in vivo, has broad implications for GRN discovery and investigation.