TY - JOUR
T1 - Reconstruction of the Global Neural Crest Gene Regulatory Network In Vivo
AU - Williams, Ruth M
AU - Candido-Ferreira, Ivan
AU - Repapi, Emmanouela
AU - Gavriouchkina, Daria
AU - Senanayake, Upeka
AU - Ling, Irving T C
AU - Telenius, Jelena
AU - Taylor, Stephen
AU - Hughes, Jim
AU - Sauka-Spengler, Tatjana
N1 - Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2019/10/21
Y1 - 2019/10/21
N2 - 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 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.
AB - 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 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.
KW - Animals
KW - Gene Expression Regulation, Developmental/genetics
KW - Gene Regulatory Networks/genetics
KW - Genetic Heterogeneity
KW - Neural Crest/embryology
KW - Transcriptional Activation/genetics
KW - Vertebrates/genetics
U2 - 10.1016/j.devcel.2019.10.003
DO - 10.1016/j.devcel.2019.10.003
M3 - Article
C2 - 31639368
SN - 1534-5807
VL - 51
SP - 255-276.e7
JO - Developmental cell
JF - Developmental cell
IS - 2
ER -