Assessing regulatory information in developmental gene regulatory networks

Abstract

Gene regulatory networks (GRNs) provide a transformation function between the static genomic sequence and the primary spatial specification processes operating development. The regulatory information encompassed in developmental GRNs thus goes far beyond the control of individual genes. We here address regulatory information at different levels of network organization, from single node to subcircuit to large-scale GRNs and discuss how regulatory design features such as network architecture, hierarchical organization, and cis-regulatory logic contribute to the developmental function of network circuits. Using specific subcircuits from the sea urchin endomesoderm GRN, for which both circuit design and biological function have been described, we evaluate by Boolean modeling and in silico perturbations the import of given circuit features on developmental function. The examples include subcircuits encoding positive feedback, mutual repression, and coherent feedforward, as well as signaling interaction circuitry. Within the hierarchy of the endomesoderm GRN, these subcircuits are organized in an intertwined and overlapping manner. Thus, we begin to see how regulatory information encoded at individual nodes is integrated at all levels of network organization to control developmental process.

Keywords: Boolean modeling; circuit function; developmental GRN; network hierarchy; network topology.

Fig. 1.

Structure and function of different types of subcircuit. (A) Positive feedback subcircuit. (B) Community-effect subcircuit. (C) Coherent feedforward subcircuit. (D) Incoherent feedforward subcircuit. (E) Mutual-repression subcircuit. (F) Double-negative gate subcircuit. All except the subcircuit in D are examples from the sea urchin endomesoderm GRN. (Left) The topologies of regulatory interactions in each subcircuit. (Right) The expression of each gene in the subcircuit under each condition, as determined by Boolean modeling. The indicated time steps do not represent real time. Blue, expression; gray, no expression. For equations and additional analyses, see SI Appendix. DN, double-negative gate; D/N, Delta/Notch signaling; Mat., maternal; Skel., skeletogenic; Ubi, ubiquitous activator.

Fig. 2.

Structure and function of signaling interactions mediated by toggle switch circuitry. Components of this subcircuit as expressed in different cellular domains are shown on top. Cells expressing wnt (A) signal to adjacent cells (B), where hox11/13b is expressed downstream of Tcf/β-catenin and Eve. In cells not receiving Wnt signaling (C), hox11/13b is repressed by Tcf/Groucho, whereas in the absence of the SRTF (D), hox11/13b expression is activated by Eve. The complete subcircuit is shown in Lower Left, and gene expression in each condition a–d as determined by Boolean modeling is shown in Lower Right. SRTF, signal response transcription factor. For model equations, see SI Appendix.

Fig. 3.

Distribution of subcircuits in the endomesoderm GRN. Subcircuits of each type identified in the endomesoderm GRN model are color-coded as follows: pink, double-negative gate; dark blue, coherent feedforward subcircuit; light blue, community-effect subcircuit; yellow, positive feedback subcircuit; green, signaling interaction; red, toggle switch circuitry; and brown, mutual-repression subcircuit. For recent updates of the endomesoderm GRN model, see grns.biotapestry.org/SpEndomes/.