Involvement Of Abnormal Expressed LncRNA In The Pathogenesis Of Monozygotic Twins Discordant For Schizophrenia

Schizophrenia(SCZ)is a severer psychiatric disorder with evidences of strong genetic and environmental components in its complex etiologies.Epigenetic modifications including DNA methylation,histone modifications and long non-coding RNA(IncRNA)are important mechanisms mediating gene-environment interaction.Several reports found aberrant expressed IncRNA in psychiatric disorders,but the mechanism remains unclear.In this study,peripheral blood RNAs from 8 pairs of monozygotic twins discordant for SCZ and healthy control were employed for RNA high-throughput sequencing.We identified that 2 differentially expressed IncRNAs were shown within the monozygotic twins discordant for SCZ,and mRNA level of 877 genes were highly correlated(|R|>0.7)with these 2 IncRNAs.Co-express network analysis of 2 IncRNA with 877 mRNAs showed that 2 IncRNAs(AC006129.1 and RP5-998N21.4)were located in the key-node of co-express network.The potential target genes of these two IncRNAs were identified from their highly correlated expressed 877 mRNAs as flows:1)two genes were identified with the highest R value in correlation analysis.2)two genes were identified with the highest fold-change value in differentially expressed mRNA analysis within discordant twins.3)eighteen genes were found to be associated with SCZ in previously reports.We further validate the relationships of these thirteen mRNAs with two IncRNAs in HEK293T and N2A cells transfected with IncRNA AC006129.1.We further observed overexpressed IncRNA AC006129.1 could up-regulate the mRNA levels of endogenous SOCS3 and CXCL5 genes in both HEK293T and N2a cells.Overexpression of IncRNA AC006129.1 in mouse displayed Ventral hippocampus(vHip)-dependent learning and memory dysfunction analyzed with Y-mase test,and medial Prefrontal Cortex(mPFC)-dependent and vHip-dependent social withdrawal and sensorimotor gating feature impairment analyzed with social interaction test and prepulse inhibition(PPI)test.In conclusion,the present study identified an overexpressed IncRNA AC006129.1 in the patients with SCZ discordant monozygotic twins,which induced learning and memory dysfunction and social withdrawal in mouse,providing plausible epigenetic evidence of lncRNA involvement in the etiology of SCZ.