Reconstruction of the Global Neural Crest Gene Regulatory Network InVivo.

Ruth M Williams,Emmanouela Repapi,Jelena Telenius,Ivan Candido-Ferreira,Irving T C Ling,Stephen Taylor,Jim Hughes,Upeka Senanayake,Tatjana Sauka-Spengler,Daria Gavriouchkina

doi:10.1016/j.devcel.2019.10.003

Ruth M Williams, Emmanouela Repapi + Show 8 more

Open Access

https://doi.org/10.1016/j.devcel.2019.10.003

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Abstract

SummaryPrecise 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 reverse engineering of 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.

Highlights

Gene regulatory networks (GRNs) are information-processing systems embedded in genomes, responsible for orchestrating cell cycle, homeostasis, physiological processes, and development (Levine and Davidson, 2005; Wyrick and Young, 2002)
We reveal direct feedforward loops controlled by the heterotypic binding of these transcription factors (TFs), as well as the negative cross-regulation of these two identities, which function as core logical features of the neural crest (NC)-GRN
At 8-10ss, in addition to bona fide NC TFs and other TFs, genes involved in cell migration (EdnrB, Cxcr4), extracellular matrix (ECM) remodeling (Adamts1/20/l1), and differentiation into various NC derivatives (Col9a3, Enc1, Ltk, RXRG) were added to the program (Figures 1E and S1B)

Summary

Introduction

Gene regulatory networks (GRNs) are information-processing systems embedded in genomes, responsible for orchestrating cell cycle, homeostasis, physiological processes, and development (Levine and Davidson, 2005; Wyrick and Young, 2002). Pioneering work on GRNs was conducted in several systems, including yeast (Lee et al, 2002), Drosophila (Sandmann et al, 2007), sea urchin embryos (Smith et al, 2007), vertebrate T-lymphocytes (Georgescu et al, 2008), and developing nervous system (Meulemans and Bronner-Fraser, 2004; Sauka-Spengler and Bronner-Fraser, 2008; Gouti et al, 2017), yielding valuable insights into the architecture, logic, modularity, and connectivity of developmental circuitries and their pivotal role in evolutionary dynamics (Davidson and Erwin, 2006). A systemslevel approach combining epigenomic and transcriptional characterization of specific cell types at population and single-cell levels is poised to resolve complex embryonic GRNs

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