A non-coding RNA risk pathway in schizophrenia in which miR-137 induces the lncRNA GOMAFU through a pathological transcription network

MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate broad gene networks through distinct mechanisms, which govern normal brain development and function but are dysregulated in schizophrenia (SCZ). However, how disease-risk miRNAs and lncRNAs co-operate to form pathogenic pathways that contribute to the complex etiology of SCZ remains poorly understood. In this study, we identified a novel miRNA-lncRNA risk pathway for SCZ in which the well-recognized SCZ-risk factor miR-137 enhances expression of the SCZ-risk lncRNA GOMAFU in human neuron development. We found vigorous upregulation of GOMAFU during the development of multiple types of human neurons in vivo and in culture . Interestingly, histone acetylation down-regulates GOMAFU in iPSC-derived human neurons, likely through inducing transcription repressors of GOMAFU, represented by the miR-137-traget E2F6. Indeed, we observed co-regulation of MIR137HG with GOMAFU during normal human neuron development and in SCZ brains and further demonstrated that miR-137 is necessary and sufficient for enhancing GOMAFU expression. Moreover, we identified transcriptomic changes induced by miR-137 in a human neuronal progenitor cell line and discovered that miR-137 integrates the functional co-operation of histone acetylation and transcription factors to drive GOMAFU expression. Strikingly, a significant number of miR-137-regulated transcription factors are predicted to bind the GOMAFU promoter and affected in SCZ brains, which form a highly interactive molecular network. Together, these studies unveil the miR-137-GOMAFU non-coding RNA pathway in human neurons connected by SCZ-affected transcription factors, providing a new mode of functional integration between non-coding and coding risk genes of SCZ that form a pathological network.