The top three predicted interactions on the four benchmark datasets.

<p>The top three predicted interactions on the four benchmark datasets.</p

A Provisional Gene Regulatory Atlas for Mouse Heart Development

<div><p>Congenital Heart Disease (CHD) is one of the most common birth defects. Elucidating the molecular mechanisms underlying normal cardiac development is an important step towards early identification of abnormalities during the developmental program and towards the creation of early intervention strategies. We developed a novel computational strategy for leveraging high-content data sets, including a large selection of microarray data associated with mouse cardiac development, mouse genome sequence, ChIP-seq data of selected mouse transcription factors and Y2H data of mouse protein-protein interactions, to infer the active transcriptional regulatory network of mouse cardiac development. We identified phase-specific expression activity for 765 overlapping gene co-expression modules that were defined for obtained cardiac lineage microarray data. For each co-expression module, we identified the phase of cardiac development where gene expression for that module was higher than other phases. Co-expression modules were found to be consistent with biological pathway knowledge in Wikipathways, and met expectations for enrichment of pathways involved in heart lineage development. Over 359,000 transcription factor-target relationships were inferred by analyzing the promoter sequences within each gene module for overrepresentation against the JASPAR database of Transcription Factor Binding Site (TFBS) motifs. The provisional regulatory network will provide a framework of studying the genetic basis of CHD.</p></div

DB Index as a function of N. N is the number of iterations of comprehensive clustering used specify each top set of co-expression gene modules.

<p>The arrow marks the lowest calculated DB Index of 4.9, where N = 520. Lower DB Index values correspond to better configuration, so the top set of clusters for N = 520 is the optimal set of co-expression gene modules.</p

The newly confirmed drug-target interactions strongly predicted by NetCBP in the dataset of GPCRs.

<p>The newly confirmed drug-target interactions strongly predicted by NetCBP in the dataset of GPCRs.</p

The optimal module set was classified into eight categories according to the phase specific expression in the modules.

<p>The table and bar plots summarize the classifications.</p

The newly confirmed drug-target interactions strongly predicted by NetCBP in the dataset of enzymes.

<p>The newly confirmed drug-target interactions strongly predicted by NetCBP in the dataset of enzymes.</p

Summary of the agreements between the inferred transcriptional regulations and the regulations obtained from ChIP-seq data in the ENCODE database for several sampled TFs.

<p>Summary of the agreements between the inferred transcriptional regulations and the regulations obtained from ChIP-seq data in the ENCODE database for several sampled TFs.</p

Prediction performances of DBSI [16], Yamanishi <i>et al.</i> (2010) [12], KBMF2K [13] and our method on the four benchmark datasets in terms of average AUC values.

<p>Prediction performances of DBSI <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062975#pone.0062975-Cheng2" target="_blank">[16]</a>, Yamanishi <i>et al.</i> (2010) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062975#pone.0062975-Yamanishi2" target="_blank">[12]</a>, KBMF2K <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062975#pone.0062975-Gnen1" target="_blank">[13]</a> and our method on the four benchmark datasets in terms of average AUC values.</p

Overrepresented pathways for P10.5 and P18.5.

<p>A. The top 25 overrepresented pathways in P10.5, where modules in this class have their highest level of expression at E10.5. Pathways in red boxes are pluripotency-related pathways enriched in P10.5 modules; pathways highlighted in yellow are also enriched in P18.5. B. The top 25 overrepresented pathways in P18.5, where modules in this class have their highest level of expression at E18.5. Pathways in blue boxes are metabolism-related pathways enriched in P18.5 modules; pathways highlighted in yellow are also enriched in P10.5.</p

Partial visualization of the TRN for mouse cardiac development.

<p>A. Sub-network structure of the TRN, focusing on the sampled TFs only. Nodes and their respective outgoing arrows are colored to help clarify arrow paths. B. An explanatory example showing TFBS non-aligned transcriptional regulations. Foxd3 and Sox2 are in a co-expression gene module (beige box) and their individual TFBS aligned gene targets Tbr1 and Syt4 are in another co-expression gene module (light blue box). As shown, Syt4 is TFBS non-aligned gene target for Foxd3 and Tbr1 is the TFBS non-aligned gene target for Sox2, as Foxd3 and Sox2 are inferred TFs regulating Tbr1-Syt4 modular transcription. More complex scenarios for explaining co-regulation for non-aligned TFBS motifs are possible. C and D show combinatorial transcriptional regulations in the TRN inferred from the integration of the inferred transcriptional regulations with documented TF protein – TF protein interactions.</p