Unbiased network modeling links cortical signaling with clock components via SHARP1, BMAL1 and PER1.

A) Depicted is the network model with the highest significance computed with all genes found to be differentially regulated in the cortex at ZT4 versus ZT16 (see. Figure 2A, Tables S1-S3 and Figure S9 for description of symbols) including SHARP1 and -2. The network connects 14 seed nodes depicted as blue circles (higher expression levels in WT are indicated by associated small red circles) extended by 13 interactors. SHARP1 and -2 are labeled by red circles; all nodes added by the algorithm are not underlined by colored circles. The structure depicts two major clusters and places the circadian regulators SHARP1 and SHARP2 as well as PER1 at central positions. The left cluster (n = 19 objects) is mainly comprised of cellular signaling components (enkephalin A, substance P both encoded by Penk and the GPCRs A2A and DRD2) and downstream effectors including negative regulators (DUSP1,6 and HSPs) as well as transcriptional mediators (e.g. FOS, EGR1, JUNB). The right cluster (n = 12) comprises central components of the molecular clock (e.g. the core clock transcription factors CLOCK, NPAS2 and BMAL1 as well as clock feedback regulators and modifiers including SHARP1 and -2, PER1 and -2, CRY1, DBP and NR1D1/Rev-ERBalpha). The extended network gene list was queried against the GeneGo database for enriched correlations with diseases (B) and biological processes (C). Among the ten most significant disease associations were nine mental or mood related disease classifications (B). Among the ten highest ranked biological processes were only circadian rhythm- (rank 1 and 2) and metabolism-associated (rank 3–8) processes (C). MeSH ID, unique Medical Subject Heading disease identifier; GO ID, unique identifier of the gene ontology biological process collection; p-values determined by hypergeometric tests.