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 used Enrichr to identify pathways associated with our panels of clustered downregulated genes from our iLINCS clustering analysis ( Figure 4 , Figures S11-S17). Using KEGG, we generated top cell signaling pathways which returned hits such as HTLV infection, hepatitis B, p53 signaling, and cell cycle pathways ( Figure S11 ). This implicates inflammation, impaired immunity, and cell proliferation. The top 5 hits in our GO cellular components analysis for panels of clustered downregulated genes implicate mitochondria and oxidative phosphorylation ( Figure S12 ). The top hits of our protein-protein interaction analysis ( Figure S14 ) for panels of clustered downregulated genes included histone deacetylase 1 (HDAC1) and HDAC2, a ubiquitously expressed protein that removes acetyl groups from lysine residues on core histones (81) . Other top hits in our protein-protein interaction analysis include proliferating cell nuclear antigen (PCNA) and BRCA1, which also bind HDAC1 and are involved in epigenetics, DNA replication, and DNA repair (82) . Interestingly, HDAC1 is increased in the prefrontal cortex and hippocampus in schizophrenia and overexpression of HDAC1 leads to impairments in working memory (83) (84) (85) . There are accumulating instances of schizophrenia patients with mutations in genes encoding chromatin regulators (such as histone modifying enzymes and transcription factors) (86) . Other hits included transcription factors involved in inflammation and the balance of activation and suppression of cellular proliferation processes.