Andrew M Shafik1, Feiran Zhang1, Zhenxing Guo2, Qing Dai3, Kinga Pajdzik3, Yangping Li1, Yunhee Kang1, Bing Yao1, Hao Wu2, Chuan He3, Emily G Allen1, Ranhui Duan4, Peng Jin5. 1. Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, 30322, USA. 2. Department of Biostatistics and Bioinformatics, School of Public Health, Emory University, Atlanta, GA, 30322, USA. 3. Department of Chemistry, University of Chicago, Chicago, IL, 60637, USA. 4. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, Hunan, China. 5. Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, 30322, USA. peng.jin@emory.edu.
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.
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.
Entities:
Keywords:
Aging; Alternative 3′UTR; Alzheimer’s; Epitranscriptomics; Neurodevelopment; Regulation of mRNA levels; Regulation of protein levels; m6A
Authors: R D Terry; E Masliah; D P Salmon; N Butters; R DeTeresa; R Hill; L A Hansen; R Katzman Journal: Ann Neurol Date: 1991-10 Impact factor: 10.422
Authors: Nian Liu; Katherine I Zhou; Marc Parisien; Qing Dai; Luda Diatchenko; Tao Pan Journal: Nucleic Acids Res Date: 2017-06-02 Impact factor: 16.971