N6-methyladenosine dynamics in neurodevelopment and aging, and its potential role in Alzheimer's disease.

BACKGROUND

N6-methyladenosine (mA) modification is known to impact many aspects of RNA metabolism, including mRNA stability and translation, and is highly prevalent in the brain.

RESULTS

We show that mA modification displays temporal and spatial dynamics during neurodevelopment and aging. Genes that are temporally differentially methylated are more prone to have mRNA expression changes and affect many pathways associated with nervous system development. Furthermore, mA shows a distinct tissue-specific methylation profile, which is most pronounced in the hypothalamus. Tissue-specific methylation is associated with an increase in mRNA expression and is associated with tissue-specific developmental processes. During the aging process, we observe significantly more mA sites as age increases, in both mouse and human. We show a high level of overlap between mouse and human; however, humans at both young and old ages consistently show more mA sites compared to mice. Differential mA sites are found to be enriched in alternative untranslated regions of genes that affect aging-related pathways. These mA sites are associated with a strong negative effect on mRNA expression. We also show that many Alzheimer-related transcripts exhibit decreased mA methylation in a mouse model of Alzheimer's disease, which is correlated with reduced protein levels.

CONCLUSIONS

Our results suggest that mA exerts a critical function in both early and late brain development in a spatio-temporal fashion. Furthermore, mA controls protein levels of key genes involved in Alzheimer's disease-associated pathways, suggesting that mA plays an important role in aging and neurodegenerative disease.