Scientists Make Learning and Memory Breakthrough

ON2018-11-12TAG: ShanghaiTech UniversityCATEGORY: School of Life Science and Technology

A team of scientists led by Dr. Zhou Tao from ShanghaiTech’s School of Life Science and Technology, Dr. He Chuan from University of Chicago and Dr. Song Hongjun from University of Pennsylvania, have made a breakthrough in the field of RNA methylation (m6a) in regulating brain functions. Their work, entitled “m6A Facilitates Hippocampus-Dependent Learning and Memory through YTHDF1” was published online in Nature on November 1st.

m6A was first discovered in 1975 and is the most prevalent internal RNA modification in mammalian mRNA. The discovery of first m6A demethylase in 2011 and the development of transcriptome-wide mapping method of m6A have sparked extensive research on the biological functions of m6A. After binding by its reader proteins, m6A affects nearly every step of RNA lifecycle and many biological processes. Among all the tissues, the brain has the most abundant distribution of m6A and its reader proteins. Whether and how m6A and its reader proteins affect specific brain functions, such as learning and memory, remains unknown. 

In order to explore the functional roles of m6A and its readers in learning and memory process, the researchers generated reader protein knock-out mice by using CRISPR/Cas9, and combined with behavior analysis, electrophysiological recording, brain region-specific over-expression or knock-down, m6A-seq, RNA-seq and CLIP-seq technologies. They found that m6A facilitates hippocampus-dependent learning and memory through its reader protein YTHDF1, and that this process is neuronal activity dependent. This is the first research to show the molecular mechanism of learning and memory at an epitranscriptome level, and has improved our knowledge of the in-vivo functions of m6A. 

Dr. Zhang Xuliang is co-first author, Dr. Zhou Tao is the last and co-corresponding author. This work was supported by grants from National Natural Science Foundation of China, National Key R&D Program of China, Shanghai Rising-Star Program and Startup Foundation of ShanghaiTech University. 

A proposed mechanism for how Ythdf1 contributes to memory formation: Ythdf1 promotes translation of m6A-modified target transcripts, including synaptic transmission and LTP-related ones,in response to learning stimulus,thus facilitating synapse strength adequately for a memory to occur