Abstract
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 (Hmgn1, Ssbp1, LOC684988, Rpl23, Gga1, Rhobtb2, Dhcr24, Atg9a, Dlgap3, Grm5, Scn2b, Furin, Sh3kbp1, Ubqln1, and Unc13a) related to the rat hippocampus developmental dysregulation, of which Hmgn1, Rhobtb2 and Unc13a related to autism, and Dlgap3, Grm5, Furin and Ubqln1 are related to Alzheimer’s disease, and schizophrenia. Transcriptional alterations of the hub genes were confirmed except for Atg9a. 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 Rhobtb2. 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.
Highlights
A multitude of epidemiological studies, which were based on the Dutch Hunger Winter Famine [1] and the Chines Famine [2] cohorts, demonstrated that maternal exposure to nutrition deficiency during critical stages of pregnancy significantly increases the risks of schizophrenia, bipolar disorder in the offspring
We did not find significant signals in the prefrontal cortex responding to maternal prenatal nutritional deficiency. 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
We demonstrated that prenatal exposure to malnutrition results in systematical changes of transcriptome and DNA methylome associated with neuropsychiatric diseases [12]
Summary
A multitude of epidemiological studies, which were based on the Dutch Hunger Winter Famine [1] and the Chines Famine [2] cohorts, demonstrated that maternal exposure to nutrition deficiency during critical stages of pregnancy significantly increases the risks of schizophrenia, bipolar disorder in the offspring. Using gene expression and DNA methylation modifications profiling strategies, we have observed significantly different patterns of gene expression and trace elements in pregnant rats of the RLP50 group This broadens our understanding of the complex biochemical perturbations that prenatal exposure to famine can induce, and these perturbations may eventually lead to impairment of fetal neurodevelopment [8]. These studies emphasized only on screening differentially expressed biomarkers rather than determining the connection between them, in which biomarkers with similar expression patterns may be functionally related. Plenty of evidence suggested the modules as stable units underlying transcriptional regulation networks whose function can remain the same while individual gene expression can be changed or replaced by other genes with similar redundant functions [11]
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