Synaptic N6-methyladenosine (m6A) epitranscriptome reveals functional partitioning of localized transcripts

Synaptic N6-methyladenosine (m6A) epitranscriptome reveals functional partitioning of localized transcripts

A localized transcriptome at the synapsefacilitates synapse-, stimulus-, and transcript-specific local protein synthesis in response to neuronal activity. While enzyme-mediated mRNA modifications are known to regulate cellular mRNA turnover, the role of these modifications in regulating synaptic RNA has not been studied. We established low-input m6A-seq of synaptosomal RNA to determine the chemically modified local transcriptome in healthy adult mouse forebrains and identified 4,469 selectively enriched m6A sites in 2,921 genes as the synaptic m6A epitranscriptome (SME). SME is functionally enriched in synthesis and modulation of tripartite synapses, and in pathways implicated in neurodevelopmental and neuropsychiatric diseases. Interrupting m6A-mediated regulation via knockdown of readers in hippocampal neurons alters expression of SME member Apc, resulting in synaptic dysfunction includingimmature spine morphology and dampened excitatory synaptic transmission concomitant with decreased PSD-95 clustering and GluA1 surface expression. Our findings indicate that chemical modifications of synaptic mRNAs critically contribute to synaptic function.

  • 著者 Daria Merkurjev, Wan-Ting Hong, Kei Iida, Ikumi Oomoto, Belinda J Goldie, Hitoshi Yamaguti, Takayuki Ohara, Shin-ya Kawaguchi, Tomoo Hirano, Kelsey C Martin, Matteo Pellegrini, Dan Ohtan Wang
  • 掲載誌 Nature Neuroscience. 2018 Jul;21(7):1004-1014