In contrast to previous studies that focused mainly on the influence of maternal malnutrition on fetal neurodevelopment
, our study provides a striking view of how the epigenetic DNA methylation landscape of the thalamus and the hippocampus in postnatal individuals is modified in response to malnourishment. We describe a genome-wide, quantitative characterization of malnourishment-induced CpG methylation changes in postnatal mice. These data may serve as a useful resource for the neuroscience community and brain science studies.
Our study demonstrated several key aspects of malnourishment-induced epigenetic DNA modifications in mice. First, the global DNA methylation status in the thalamus and the hippocampus of postnatal malnourished mice and normal mice had significant differences. This told us that the mechanism of the malnourishment-induced epigenetic DNA modifications in the thalamus was different from the hippocampus. Second, our analysis revealed specific characteristics of the genomic DNA methylation distribution in the thalamus and the hippocampus of malnourished mice and normal mice. Third, our MSCC results provided direct profiling regarding the malnourishment-induced DNA methylation changes in both the thalamus and the hippocampus. Fourth, our study provided a large number of genes that were subjected to modulation by malnourishment at the level of DNA modification. The majority of these genes were associated with neuronal occurrence and development.
CpG-rich regions of DNA are known as CpG islands (CGIs), and most CGIs remain unmethylated
. Moreover, approximately 60% of mammalian genes have CGI promoters, and methylated CGIs play an important role in gene silencing during processing
. The best-known producer of epigenesis, DNA methylation, plays an important role in regulating gene expression to preserve local activity states
. Epigenesis is defined as heritable changes in gene expression that are not accompanied by changes in DNA sequence
. Thus, to reflect the DNA methylation landscape and distribution, we measured the methylation level in different regions of the genome. To gain more insight into whether the changes caused by methylation were present on the gene expression level, we performed comparisons between our MSCC data and the gene expression data (GDS1490). All our results were in accordance with the theoretical basic characteristics of DNA methylation modification in mammals, which confirmed the accuracy of our experiment.
It should be noted that when we used our criteria (∆MSCC > 25%) to screen out differential genes in the normal and famine groups, no genes were selected in the hippocampus, while 500 distinct genes were revealed in the thalamus. This may due to the selected CCGG methylated level in the hippocampus, which was much lower than that in the thalamus. Thus, a methylation level of >25% was difficult to achieve in the hippocampus. In this regard, further study of the hippocampus, which has vital roles in brain development, cognition, learning, and memory
, would provide valuable information.
In the thalamus, the most significant identified relative pathway was long-term potentiation. It is a major form of long-lasting synaptic plasticity in the mammalian brain, which occurs by increasing synaptic strength, and is involved in information storage, and therefore, in learning and memory
. Ppp1r1a, Ppp3r1, Raf1, Camk2b, Ppp3ca, Prkacb, Cacna1c, Plcb1, and Calm2 were the filtered genes in this pathway from our study. These genes are critically involved in neuronal formation and development. Among the 9 genes, Camk2b plays important roles in brain synaptic plasticity
. Ppp3ca is a tumor suppressor gene that functions in Alzheimer’s disease
[25, 26]. Prkacb is a protein kinase and is related to Alzheimer’s disease
. Plcb1 is of critical importance in codifying neurotransmitter receptors and is associated with schizophrenia
[46, 47]. It is particularly noteworthy that the calcium channel, voltage-dependent, L-type, alpha 1C subunit (Cacna1c) gene contributes to many psychiatric disorders
[55, 56], specifically schizophrenia
[40–42] and bipolar disorder
Our study considered the global DNA methylation status of the thalamus and the hippocampus and provides a DNA methylation landscape of these two brain regions after they were modified by malnutrition. It also implicates DNA modification as an effective epigenetic regulator in postnatal brain maturation. Our data also indicate that malnutrition in postnatal individuals may increase the risk of developing psychiatric disorders such as Alzheimer’s disease, schizophrenia and bipolar disorder. Nonetheless, we believe that much more research on the functional verification of the related genes is necessary to obtain a better understanding of the pathogenesis of malnutrition.