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. 2007 Jul;17(7):1061-71.
doi: 10.1101/gr.6148107. Epub 2007 May 18.

Transcription factor modularity in a gene-centered C. elegans core neuronal protein-DNA interaction network

Vanessa Vermeirssen  1 , M Inmaculada Barrasa, César A Hidalgo, Jenny Aurielle B Babon, Reynaldo Sequerra, Lynn Doucette-Stamm, Albert-László Barabási, Albertha J M Walhout
Affiliations

Transcription factor modularity in a gene-centered C. elegans core neuronal protein-DNA interaction network

Vanessa Vermeirssen et al. Genome Res. 2007 Jul.

Abstract

Transcription regulatory networks play a pivotal role in the development, function, and pathology of metazoan organisms. Such networks are comprised of protein-DNA interactions between transcription factors (TFs) and their target genes. An important question pertains to how the architecture of such networks relates to network functionality. Here, we show that a Caenorhabditis elegans core neuronal protein-DNA interaction network is organized into two TF modules. These modules contain TFs that bind to a relatively small number of target genes and are more systems specific than the TF hubs that connect the modules. Each module relates to different functional aspects of the network. One module contains TFs involved in reproduction and target genes that are expressed in neurons as well as in other tissues. The second module is enriched for paired homeodomain TFs and connects to target genes that are often exclusively neuronal. We find that paired homeodomain TFs are specifically expressed in C. elegans and mouse neurons, indicating that the neuronal function of paired homeodomains is evolutionarily conserved. Taken together, we show that a core neuronal C. elegans protein-DNA interaction network possesses TF modules that relate to different functional aspects of the complete network.

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Figures

Figure 1.
Figure 1.
A C. elegans core neuronal PDI network. (A) The core neuronal PDI network visualized using Cytoscape v2.3 (for a larger depiction, see Supplemental Fig. S4). (B) From PDIs to transcription regulatory interactions by data integration. (Top) Three autoregulatory PDIs confirmed proposed regulatory interactions. DAF-19 was proposed to regulate its own expression because the daf-19 promoter contains a predicted DAF-19 binding site (RFX box). (Middle) Two new PDIs may be involved in the determination of bilateral asymmetry in neurons. (Bottom) Two putative interologs/regulogs. Dotted lines with arrow (activation) or blunt arrow (repression), regulation; solid lines with dotted arrow, physical interaction.
Figure 2.
Figure 2.
The core neuronal PDI network is enriched for paired homeodomains. The percentage of the different DNA-binding domains in TFs retrieved in the core neuronal PDI network versus all C. elegans TFs. The network is significantly enriched for TFs that possess a homeodomain (HD, P < 0.001), particularly paired homeodomains (HD-PRD, inset, P < 0.001), and is significantly depleted for nuclear hormone receptors (ZF-NHR, P < 0.001).
Figure 3.
Figure 3.
Architecture of the C. elegans core neuronal PDI network. (A) Out-degree distribution. Logarithmic binning was applied to fit a power law to P(kout): P(kout) = 0.69k−2.05 (R2 = 0.99; inset). (B) In-degree distribution. Logarithmic binning was applied to fit a power law with saturation to P(kin) = 1093.2*(10.83 + k)−3.30(R2 = 0.97; inset). (C) Interactor hubs in the core neuronal PDI network have a similar out-degree in the digestive tract PDI network (diagonal). Interactors specific for each network are localized on the axes. The colors indicate the number of interactors per feature.
Figure 4.
Figure 4.
The core neuronal PDI network contains two specifier TF modules. (A) From a PDI network to a topological overlap network. (B) Topological overlap matrix for the interactors using the geometric formula and the resulting topological overlap network for interactor pairs with a topological coefficient ≥0.2. (Pink) Interactors in module 1 that connect to the promoter hubs Pdaf-3, Pcog-1, and Pnhr-79; (green) interactors in module 2 that bind the promoter hub Punc-30, in addition to Pceh-23, Pnhr-83, PT22H9.4, Pnhr-41, Pttx-1, Pdaf-19, Phlh-2, Pnhr-6, or Plin-32. (See Supplemental Fig. 5 for the modules obtained with the meet/min formula.) (C) PDI network corresponding to the interactors indicated in B. (Red) Paired homeodomain; (orange) other homeodomain, (R) reproduction; (B) response to stimulus (behavior). The average outgoing degree is indicated.
Figure 5.
Figure 5.
Homeodomain TFs are neuronally expressed both in C. elegans and in mouse. (A) Association analysis between TF family and expression patterns in C. elegans. (B) Association analysis between TF family and expression profiles in mouse. P-values were calculated by a two-tailed test, as well as by a right- and left-tailed test for enrichment and depletion, respectively. We only show the latter values, and indicate with an asterisk when there was a slight enrichment/depletion for which the two-tailed test was not significant.
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