Abstract
Grouping genes by similarity of expression across multiple cellular conditions enables the identification of cellular modules. The known functions of genes enable the characterization of the aggregate biological functions of these modules. In this paper, we use a high-throughput approach to identify the effective mutual regulatory interactions between modules composed of mouse genes from the Alliance for Cell Signaling (AfCS) murine B-lymphocyte database which tracks the response of ∼15,000 genes following chemokine perturbation. This analysis reveals principles of cellular organization that we discuss along four conceptual axes. (1) Regulatory implications: the derived collection of influences between any two modules quantifies intuitive as well as unexpected regulatory interactions. (2) Behavior across scales: trends across global networks of varying resolution (composed of various numbers of modules) reveal principles of assembly of high-level behaviors from smaller components. (3) Temporal behavior: tracking the mutual module influences over different time intervals provides features of regulation dynamics such as duration, persistence, and periodicity. (4) Gene Ontology correspondence: the association of modules to known biological roles of individual genes describes the organization of functions within coexpressed modules of various sizes. We present key specific results in each of these four areas, as well as derive general principles of cellular organization. At the coarsest scale, the entire transcriptional network contains five divisions: two divisions devoted to ATP production/biosynthesis and DNA replication that activate all other divisions, an “extracellular interaction” division that represses all other divisions, and two divisions (proliferation/differentiation and membrane infrastructure) that activate and repress other divisions in specific ways consistent with cell cycle control.
Highlights
The importance of modular organization in biology is widely appreciated [1,2,3,4,5,6] and is manifested in conserved gene modules across species [7,8,9]
Regulatory Implications The mutual regulatory influences for networks comprising n 1⁄4 12, 20, 42, and 72 cellular modules are shown in Figure 2 for the 1.5-h time-interval (Table S3)
These effective regulatory influences between modules are composed of direct and indirect causal mechanisms as well as temporally correlated effects that are seen across all 33 perturbations
Summary
The importance of modular organization in biology is widely appreciated [1,2,3,4,5,6] and is manifested in conserved gene modules across species [7,8,9]. High-throughput data has yielded progress in molecular-level descriptions of interactions of genes, proteins, and metabolites [10,11,12,13,14]; understanding an entire cell or its major components from genetic information is a major methodological challenge [15]. We use genome-wide expression Alliance for Cell Signaling (AfCS) data to first empirically obtain modular functions and empirically obtain the effective inhibitory and activating regulatory influences between these modules at many scales of resolution (see Figure 1). This approach yields copious results about effective regulatory interactions so that a complete discussion is not possible in a single manuscript.
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