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

Genome Biology

Ranhui Duan¹  Hao Wu²  Zhenxing Guo²  Qing Dai³  Kinga Pajdzik³  Chuan He³  Emily G. Allen⁴  Feiran Zhang⁴  Bing Yao⁴  Yunhee Kang⁴  Yangping Li⁴  Andrew M. Shafik⁴  Peng Jin⁴ 

[1] Center for Medical Genetics, School of Life Sciences, Central South University;Department of Biostatistics and Bioinformatics, School of Public Health, Emory University;Department of Chemistry, University of Chicago;Department of Human Genetics, School of Medicine, Emory University;

关键词: Epitranscriptomics;    m6A;    Neurodevelopment;    Aging;    Alzheimer’s;    Regulation of mRNA levels;   

DOI  :  10.1186/s13059-020-02249-z

来源: DOAJ

【 摘 要 】

Abstract Background N6-methyladenosine (m6A) 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 m6A 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, m6A 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 m6A 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 m6A sites compared to mice. Differential m6A sites are found to be enriched in alternative untranslated regions of genes that affect aging-related pathways. These m6A sites are associated with a strong negative effect on mRNA expression. We also show that many Alzheimer-related transcripts exhibit decreased m6A methylation in a mouse model of Alzheimer’s disease, which is correlated with reduced protein levels. Conclusions Our results suggest that m6A exerts a critical function in both early and late brain development in a spatio-temporal fashion. Furthermore, m6A controls protein levels of key genes involved in Alzheimer’s disease-associated pathways, suggesting that m6A plays an important role in aging and neurodegenerative disease.

【 授权许可】

Unknown