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

Next, we probed for kinases that when knocked down in specific cell lines, decreased the expression of genes that were in our panels of clustered downregulated genes ( Figure S15 ). We The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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 found multiple kinases with important roles in glucose homeostasis and energy metabolism. The nuclear receptor PPARγ forms a heterodimer with the retinoid X receptor (RXR), two of our top hits, increasing the transcription of various genes that stimulate glucose uptake and carbohydrate metabolism (87) . PPARγ ligands such as thiazolidinediones (TZDs) increase glucose utilization, treat hyperglycemia, and represent therapeutic possibilities in diseases with deficient glycolytic systems (88) . We also found kinases that are involved in axonal growth during CNS development (RYK), cell growth and cycle progression (WEE1, ABL2), and cytoskeletal remodeling (ABL2). Finally, we performed pathway analyses to identify transcription factors with occupancy sites for our panels of clustered downregulated genes, several of which played key roles in cellular proliferation/development and were similar to hits from previous analyses (MYC, MYCN, NUCKS1, forkhead box M1) ( Figure S16 ). Enrichr analyses are summarized in Table 3 and a full discussion of panels of clustered downregulated genes can be found in the supplement.