Figure 3.
Top ranking gene networks. (a) The first score (by P-value) network from the study. Reference genes are marked with red circles. The network is centered on the c-Myc gene hub. C-myc is known as a proto-oncogene and is associated with cell proliferation and as a pro-apoptotic molecule. (b) The second scoring (by P-value) network from the study. The network includes 10 reference genes that are marked with red circles. The network is centered on the PPARG (human accelerated region 20 (HAR20)). Peroxisome proliferator-activated receptor-gamma (PPAR-γ) is a transcriptional coactivator involved in the regulation of energy metabolism and in mitochondrial biogenesis. Importantly, the gene has a role in the regulation of cAMP response element-binding protein (CREB). The transcription factor CREB has been implicated in signaling pathways relevant for pathogenesis and therapy of depression, which includes the c-Jun N-terminal kinases (JNKs). (c) Merging of the two top-ranking networks ranked by P-value reveal that the two central gene hubs (c-MYC and PPAR-γ) are linked by the activator protein (AP)-1-binding hub. The AP-1 is associated with dimeric transcription factors composed of Jun and Fos subunit. The Ap-1 target is particularly relevant for depression as it regulates gene expression in response to different stimuli including cytokines. Together with the nuclear factor (NF)-kappaB, AP-1 controls T-cell activation, followed by binding of foreign antigens to the T-cell receptor leading to cytokine secretion. AP-1 therefore has a key role in the initiation inflammatory response by activating immune cells through expression and secretion of chemokines and cytokines. Inflammation is an event that has been associated with increased risk of major depressive episodes. Higher levels of peripheral inflammatory markers taken from blood samples have been found in depressed patients.