A non-coding RNA risk pathway in schizophrenia: miR-137 enhances 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 in SCZ brains remain poorly understood. In this study, we identified a novel miRNA-lncRNA pathway in which the well-recognized SCZ-risk factor miR-137 enhances expression of the SCZ-risk lncRNA GOMAFU in human neuron development. We found significant up-regulation of GOMAFU during differentiation of multiple types of human neurons in vivo and in culture. Interestingly, the accumulation of histone acetylation, which activates numerous neuronal genes, down-regulates GOMAFU in iPSC-derived human neurons through inducing transcription repressors of GOMAFU, represented by the miR-137-target E2F6. We further demonstrated that miR-137 is necessary and sufficient for enhancing GOMAFU expression in a human neuronal progenitor cell (NPC) line and observed co-regulation of MIR137 with GOMAFU during normal human neuronal development and in SCZ brains. Moreover, we identified human NPC transcriptomic changes induced by miR-137 and discovered that miR-137 integrates functional co-operation of histone acetylation and transcription factors to promote GOMAFU expression. Notably, a significant number of miR-137-regulated transcription factors are predicted to bind the GOMAFU promoter and affected in SCZ brains, forming a highly interactive molecular network. Together, these results unveil the SCZ risk miR-137-GOMAFU non-coding RNA pathway connected by SCZ-affected transcription factors, providing a new mode of functional integration of non-coding and coding risk genes of SCZ that contributes to the complex etiology.