Connectivity analyses of bioenergetic changes in schizophrenia: Identification of novel treatments

Courtney R. Sullivan; Catharine A. Mielnik; Sinead M. O’Donovan; Adam J. Funk; Eduard Bentea; Erica A.K. DePasquale; Zhexing Wen; Vahram Haroutunian; Pavel Katsel; Amy J. Ramsey; Jarek Meller; Robert E. McCullumsmith

We began by using Enrichr to identify pathways associated with our panels of clustered upregulated genes from our iLINCS clustering analysis ( Figure 3 , Figures S4-S10). Using KEGG, we generated top cell signaling pathways which returned hits such as FOXO, Wnt, and MAPK signaling. These signaling pathways implicate glucose utilization, energy homeostasis, mitochondrial function, and cell growth. Our top protein-protein interaction hits (RPS6KA3, MAPK14, glycogen synthase kinase 3 beta (GSK3B) and cyclin dependent kinase 1 (CDK1), etc.) suggest a role for pathways involved in energy metabolism and cell proliferation. Next, we probed for kinases that when knocked down in specific cell lines, increased the expression of genes that were in our panels of clustered upregulated genes. We found several serine/threonine-protein kinases including AKT1, PTK2, MAP2K2, and ATR. AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) thought to regulate metabolism and promote cellular proliferation (76) . We also had significant hits for G-protein coupled receptor proteins NMUR2 and FFAR1. Neuromedin U (NMUR2) encodes a G-protein coupled receptor protein widely expressed in the central nervous system (CNS) that binds the neuropeptide neuromedin U in order to regulate energy homeostasis (77, 78) . These results suggest that kinases involved in glucose metabolism and cell cycle regulation are relevant to our panels of clustered upregulated genes. Finally, we performed pathway analyses to identify . CC-BY-NC-ND 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/338392 doi: bioRxiv preprint transcription factors with occupancy sites for our panels of clustered upregulated genes, several of which played key roles in neurodevelopment (WT1, NFIB, TCF3, TRIM28, etc.). Our transcription factor analysis also generated hits for estrogen receptors (ESR1, ESR2), tumor suppressors/activators (ELK3), and transcription factors involved in immune responses and macrophage function (CEBPB) (79, 80) . Enrichr analyses are summarized in Table 3 and a full discussion of panels of clustered upregulated genes can be found in the supplement.