An in-silico approach for discovery of microRNA-TF regulation of DISC1 interactome mediating neuronal migration

Abstract

Neuronal migration constitutes an important step in corticogenesis; dysregulation of the molecular mechanisms mediating this crucial step in neurodevelopment may result in various neuropsychiatric disorders. By curating experimental data from published literature, we identified eight functional modules involving Disrupted-in-schizophrenia 1 (DISC1) and its interacting proteins that regulate neuronal migration. We then identified miRNAs and transcription factors (TFs) that form functional feedback loops and regulate gene expression of the DISC1 interactome. Using this curated data, we conducted in-silico modeling of the DISC1 interactome involved in neuronal migration and identified the proteins that either facilitate or inhibit neuronal migrational processes. We also studied the effect of perturbation of miRNAs and TFs in feedback loops on the DISC1 interactome. From these analyses, we discovered that STAT3, TCF3, and TAL1 (through feedback loop with miRNAs) play a critical role in the transcriptional control of DISC1 interactome thereby regulating neuronal migration. To the best of our knowledge, regulation of the DISC1 interactome mediating neuronal migration by these TFs has not been previously reported. These potentially important TFs can serve as targets for undertaking validation studies, which in turn can reveal the molecular processes that cause neuronal migration defects underlying neurodevelopmental disorders. This underscores the importance of the use of in-silico techniques in aiding the discovery of mechanistic evidence governing important molecular and cellular processes. The present work is one such step towards the discovery of regulatory factors of the DISC1 interactome that mediates neuronal migration.