Genetic regulatory subnetworks and key regulating genes in rat hippocampus perturbed by prenatal malnutrition: implications for major brain disorders.

OBJECTIVE

Many population studies have shown that maternal prenatal nutrition deficiency may increase the risk of neurodevelopmental disorders in their offspring, but its potential transcriptomic effects on brain development are not clear. We aimed to investigate the transcriptional regulatory interactions between genes in particular pathways responding to the prenatal nutritional deficiency and to explore their effects on neurodevelopment and related disorders.

RESULTS

We identified three modules in rat hippocampus responding to maternal prenatal nutritional deficiency and found 15 key genes () related to the rat hippocampus developmental dysregulation, of which and related to autism, and and are related to Alzheimer's disease, and schizophrenia. Transcriptional alterations of the hub genes were confirmed except for . Additionally, through modeling miRNA-mRNA-transcription factor interactions for the hub genes, we confirmed a transcription factor, Cebpa, is essential to regulate the expression of . We did not find singificent singals in the prefrontal cortex responding to maternal prenatal nutritional deficiency.

CONCLUSION

These findings demonstrated that these genes with the three modules in rat hippocampus involved in synaptic development, neuronal projection, cognitive function, and learning function are significantly enriched hippocampal CA1 pyramidal neurons and suggest that three genetic regulatory subnetworks and thirteen key regulating genes in rat hippocampus perturbed by a prenatal nutrition deficiency. These genes and related subnetworks may be prenatally involved in the etiologies of major brain disorders, including Alzheimer's disease, autism, and schizophrenia.

METHODS

We compared the transcriptomic differences in the hippocampus and prefrontal cortex between 10 rats with prenatal nutritional deficiency and 10 rats with prenatal normal chow feeding by differential analysis and co-expression network analysis. A network-driven integrative analysis with microRNAs and transcription factors was performed to define significant modules and hub genes responding to prenatal nutritional deficiency. Meanwhile, the module preservation test was conducted between the hippocampus and prefrontal cortex. Expression levels of the hub genes were further validated with a quantitative real-time polymerase chain reaction based on additional 40 pairs of rats.