A novel microRNA and transcription factor mediated regulatory network in schizophrenia

Abstract

Background: Schizophrenia is a complex brain disorder with molecular mechanisms that have yet to be elucidated. Previous studies have suggested that changes in gene expression may play an important role in the etiology of schizophrenia, and that microRNAs (miRNAs) and transcription factors (TFs) are primary regulators of this gene expression. So far, several miRNA-TF mediated regulatory modules have been verified. We hypothesized that miRNAs and TFs might play combinatory regulatory roles for schizophrenia genes and, thus, explored miRNA-TF regulatory networks in schizophrenia.

Results: We identified 32 feed-forward loops (FFLs) among our compiled schizophrenia-related miRNAs, TFs and genes. Our evaluation revealed that these observed FFLs were significantly enriched in schizophrenia genes. By converging the FFLs and mutual feedback loops, we constructed a novel miRNA-TF regulatory network for schizophrenia. Our analysis revealed EGR3 and hsa-miR-195 were core regulators in this regulatory network. We next proposed a model highlighting EGR3 and miRNAs involved in signaling pathways and regulatory networks in the nervous system. Finally, we suggested several single nucleotide polymorphisms (SNPs) located on miRNAs, their target sites, and TFBSs, which may have an effect in schizophrenia gene regulation.

Conclusions: This study provides many insights on the regulatory mechanisms of genes involved in schizophrenia. It represents the first investigation of a miRNA-TF regulatory network for a complex disease, as demonstrated in schizophrenia.

Figure 1

An overview of miRNAs, TFBSs/TFs and their regulatory network in schizophrenia. SZ: schizophrenia; FFL: feed-forward loop.

Figure 2

Schizophrenia candidate genes targeted by schizophrenia related miRNAs. To simply the figure, miRNA family names are used for their precursors.

Figure 3

A miRNA and TF mediated regulatory network in schizophrenia. Red: schizophrenia related miRNAs; green: schizophrenia candidate genes; blue: TFs. Three thick lines denote regulations with experimental evidence.

Figure 4

Model of EGR3 and miRNAs involving in signaling pathways and regulatory networks in schizophrenia and nervous system. Binding of neurotrophins (BDNF or NGF) to Trk receptors activates multiple signaling pathways, including Ras/MAPK cascade, PKC, PI3K/AKT, and IP3/calcium signaling [72,73]. Stimulation of NRG1 activates MAPK and PI3K/AKT pathways [74]. These signal transductions trigger activation of several TFs such as CREB, CBP, EGR1 and EGR3, which subsequently activate their target genes (e.g., EGR3, BCL2 and NPY). Calcium influx through NMDARs activates calcineurin/NFAT signaling pathway, then activates target genes such as EGR3 [46,49]. EGR3 regulates its target genes (e.g., GABRA4, ARC and NGFR) and miRNAs (e.g., hsa-miR-195 and hsa-miR-20b).