Nature Aging: Revealing The Apparent Transcriptome Mechanism Of Regulating Primate Organ Aging

M6A is the most common type of chemical modification on eukaryotic cell mRNA, and its establishment, reading and erasure are respectively dynamically and reversibly regulated by the corresponding methylase (writer), binding protein (reader) and demethylase (eraser). Research has shown that m6A can participate in regulating various physiological or pathological processes in the body, including embryonic development, tumor development, and neurodegenerative diseases, by regulating mRNA splicing, nucleation, stability, and translation throughout its lifecycle activities. However, the regulatory role and key molecular mechanisms of m6A in maintaining organ homeostasis during physiological aging remain to be elucidated.
Liu Guanghui's research group and Qu Jing's research group of the Institute of Zoology of the Chinese Academy of Sciences, together with Ciweimin's research group and Zhang Weiqi's research group of the Beijing Institute of Genomics, published a research paper entitled m6A epigenetic regulation of tissue homeostasis during primitive aging online on Nature Aging. In this study, we used the multiple organ research model of non-human primate (cynomolgus monkey) physiological aging, combined with the research system based on genome editing and human stem cell directional differentiation, and systematically mapped the dynamic map of RNA m6A modification in the process of organ and cell aging, analyzed the changes of RNA methylation modification and related gene expression homeostasis, and explored the new mechanism of METTL3 – m6A – NPNT pathway regulating skeletal muscle aging.
This study found through systematic histological analysis of the liver, skeletal muscle, and heart of young and elderly crab eating monkeys that increased fat accumulation, upregulation of inflammatory factors, and downregulation of lamin B1 are common characteristics of aging in the three tissues; The study also found tissue specific aging related degenerative changes such as increased apoptotic cells in skeletal muscle, muscle fiber atrophy, and myocardial fiber hypertrophy in the heart. Furthermore, the correlation between m6A modification and gene expression homeostasis, as well as the regulation of aging in different tissues, were revealed through the joint analysis of m6A apparent modification maps and corresponding transcriptome maps of the three tissues. Compared to the liver and heart, studies specifically detected a decrease in overall m6A modification and a decrease in core methyltransferase METTL3 expression levels in skeletal muscle. Furthermore, through CRIPSR/Cas9 technology, METTL3 knockout myotube cells derived from human embryonic stem cells were established. It was found that the absence of METTL3 leads to degenerative changes such as atrophy, apoptosis, and accelerated aging in myotube cells, consistent with the phenotype of aging skeletal muscles. Further mechanism studies showed that NPNT, as a downstream effector of METTL3, played a role in maintaining the stability of skeletal muscle cells, while Lentivirus vector mediated METTL3 or NPNT complement expression could delay the aging of human myotube cells to a certain extent. Finally, through treatment with METTL3 enzyme activity inhibitors and overexpression of METTL3 enzyme activity mutants, the study confirmed that METTL3 promotes the expression of NPNT and maintains the homeostasis of myotube cells in a m6A dependent manner. It was also found that the m6A binding protein IGF2BP1 can bind and stabilize NPNT mRNA modified by m6A.
In summary, this study reveals the dynamic m6A modification changes in three important primate organs/tissues during physiological aging and their relationship with gene expression homeostasis, and elucidates the role and mechanism of the METTL3-m6A-NPNT pathway in maintaining human skeletal muscle homeostasis. The research has deepened scientists' understanding of the involvement of m6A in maintaining the homeostasis of human organ function and the epigenetic transcriptional regulation mechanism of aging. It provides a systematic platform for effectively integrating primate organ models and human stem cell derivative systems to explore skeletal muscle aging, and provides potential molecular targets and intervention strategies for delaying skeletal muscle aging or treating age-related skeletal muscle degenerative diseases such as sarcopenia.
The work was completed by the Institute of Zoology, Beijing Institute of Genomics, Chinese Academy of Sciences Stem Cells and regenerative medicine Innovation Institute, Capital Medical University Xuanwu Hospital, etc. The research work has received support from the Ministry of Science and Technology, the National Natural Science Foundation of China, and the Chinese Academy of Sciences.