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

被引:154
|
作者
Merkurjev, Daria [1 ]
Hong, Wan-Ting [2 ]
Iida, Kei [3 ]
Oomoto, Ikumi [2 ,4 ]
Goldie, Belinda J. [2 ,5 ]
Yamaguti, Hitoshi [2 ,6 ]
Ohara, Takayuki [2 ,4 ]
Kawaguchi, Shin-ya [7 ,8 ]
Hirano, Tomoo [8 ]
Martin, Kelsey C. [9 ,10 ,11 ]
Pellegrini, Matteo [12 ]
Wang, Dan Ohtan [2 ,13 ]
机构
[1] Univ Calif Los Angeles, Stat Dept, Los Angeles, CA USA
[2] Kyoto Univ, Inst Integrated Cell Mat Sci ICeMS, Kyoto, Japan
[3] Kyoto Univ, Grad Sch Med, Med Res Support Ctr, Kyoto, Japan
[4] Kyoto Univ, Grad Sch Biostudies, Kyoto, Japan
[5] JSPS, Tokyo, Japan
[6] Kyoto Univ, Undergrad Sch Informat & Math Sci, Kyoto, Japan
[7] Kyoto Univ, Soc Acad Collaborat Innovat, Kyoto, Japan
[8] Kyoto Univ, Grad Sch Sci, Kyoto, Japan
[9] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA
[10] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA
[11] Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA USA
[12] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA USA
[13] Kyoto Univ, Keihanshin Consortium Fostering Next Generat Glob, Kyoto, Japan
基金
日本学术振兴会;
关键词
MESSENGER-RNA METHYLATION; AUTISM SPECTRUM DISORDER; PRESYNAPTIC ACTIVE ZONE; ADENOMATOUS POLYPOSIS; GENE-EXPRESSION; ENRICHMENT ANALYSIS; OL-PROTOCADHERIN; FAT MASS; PROTEIN; TRANSLATION;
D O I
10.1038/s41593-018-0173-6
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
A localized transcriptome at the synapse facilitates 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 m(6)A-sequencing of synaptosomal RNA to determine the chemically modified local transcriptome in healthy adult mouse forebrains and identified 4,469 selectively enriched m(6)A sites in 2,921 genes as the synaptic m(6)A epitranscriptome (SME). The SME is functionally enriched in synthesis and modulation of tripartite synapses and in pathways implicated in neurodevelopmental and neuropsychiatric diseases. Interrupting m(6)A-mediated regulation via knockdown of readers in hippocampal neurons altered expression of SME member Apc, resulting in synaptic dysfunction including immature spine morphology and dampened excitatory synaptic transmission concomitant with decreased clusters of postsynaptic density-95 (PSD-95) and decreased surface expression of AMPA receptor subunit GluA1. Our findings indicate that chemical modifications of synaptic mRNAs critically contribute to synaptic function.
引用
收藏
页码:1004 / +
页数:15
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