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

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

doi:10.1038/s41593-018-0173-6

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

Nat Neurosci. 2018 Jul;21(7):1004-1014. doi: 10.1038/s41593-018-0173-6. Epub 2018 Jun 27.

Authors

Daria Merkurjev¹, Wan-Ting Hong², Kei Iida³, Ikumi Oomoto^{2

4}, Belinda J Goldie^{2

5}, Hitoshi Yamaguti^{2

6}, Takayuki Ohara^{2

4}, Shin-Ya Kawaguchi^{7

8}, Tomoo Hirano⁸, Kelsey C Martin^{9

10

11}, Matteo Pellegrini¹², Dan Ohtan Wang^{13

14}

Affiliations

¹ Statistics Department, University of California at Los Angeles, Los Angeles, CA, USA.
² Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kyoto, Japan.
³ Medical Research Support Center of Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁴ Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
⁵ Japan Society for the Promotion of Science (JSPS), Tokyo,, Japan.
⁶ Undergraduate School of Informatics and Mathematical Science, Kyoto University, Kyoto, Japan.
⁷ Society-Academia Collaboration for Innovation, Kyoto University, Kyoto, Japan.
⁸ Graduate School of Science, Kyoto University, Kyoto, Japan.
⁹ Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, CA, USA.
¹⁰ Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA, USA.
¹¹ Department of Biological Chemistry, University of California at Los Angeles, Los Angeles, CA, USA.
¹² Department of Molecular, Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, CA, USA.
¹³ Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kyoto, Japan. dwang@icems.kyoto-u.ac.jp.
¹⁴ The Keihanshin Consortium for Fostering the Next Generation of Global Leaders in Research (K-CONNEX), Kyoto University, Kyoto, Japan. dwang@icems.kyoto-u.ac.jp.

PMID: 29950670
DOI: 10.1038/s41593-018-0173-6

Abstract

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 m⁶A-sequencing 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). The 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 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / genetics
Adenosine / metabolism
Animals
Mice
Prosencephalon / metabolism*
Synapses / physiology*
Synaptic Transmission / physiology*
Transcriptome

Substances

N-methyladenosine
Adenosine