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Discovery of synapse-specific RNA N6-methyladenosine readers associated with the consolidation of fear extinction memory

View ORCID ProfileSachithrani U. Madugalle, View ORCID ProfileWei-Siang Liau, Qiongyi Zhao, Xiang Li, Hao Gong, View ORCID ProfilePaul R. Marshall, Ambika Periyakaruppiah, View ORCID ProfileEsmi L. Zajackowski, Laura J. Leighton, Haobin Ren, View ORCID ProfileMason Musgrove, Joshua Davies, View ORCID ProfileSimone Rauch, Chuan He, Bryan C. Dickinson, View ORCID ProfileLee Fletcher, View ORCID ProfileBarbora Fulopova, Stephen R. Williams, Robert C. Spitale, Timothy W. Bredy
doi: https://doi.org/10.1101/2022.06.07.495230
Sachithrani U. Madugalle
1Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
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  • ORCID record for Sachithrani U. Madugalle
Wei-Siang Liau
1Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
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Qiongyi Zhao
1Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
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Xiang Li
2Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China
3Medical Research Institute, Wuhan University, Wuhan, China
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Hao Gong
1Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
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Paul R. Marshall
1Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
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Ambika Periyakaruppiah
1Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
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Esmi L. Zajackowski
1Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
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Laura J. Leighton
1Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
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Haobin Ren
1Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
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Mason Musgrove
1Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
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Joshua Davies
1Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
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Simone Rauch
4Department of Chemistry, The University of Chicago, Chicago, USA
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Chuan He
4Department of Chemistry, The University of Chicago, Chicago, USA
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Bryan C. Dickinson
4Department of Chemistry, The University of Chicago, Chicago, USA
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Lee Fletcher
5Synaptic Integration Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
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Barbora Fulopova
5Synaptic Integration Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
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Stephen R. Williams
5Synaptic Integration Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
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Robert C. Spitale
6Department of Pharmaceutical Sciences, The University of California, Irvine, USA
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Timothy W. Bredy
1Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
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  • For correspondence: t.bredy@uq.edu.au
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Summary

The RNA modification N6-methyladenosine (m6A) is critically involved in the regulation of gene activity underlying experience-dependent plasticity, and is necessary for the functional interplay between RNA and RNA binding proteins (RBPs) in the nucleus. However, the complete repertoire of m6A-modified RNA interacting RBPs in the synaptic compartment, and whether they are involved in fear extinction, have yet to be revealed. Using RNA immunoprecipitation followed by mass spectrometry, we discovered 12 novel, synapsespecific, learning-induced m6A readers in the medial prefrontal cortex of male C57/B6 mice. m6A RNA-sequencing also revealed a unique population of learning-related m6A-modified RNAs at the synapse, which includes a variant of the long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (Malat1). m6A-modified Malat1 binds to a subset of novel m6A readers, including cytoplasmic FMR1 interacting protein 2 (CYFIP2) and dihydropyrimidase-related protein 2 (DPYSL2) and a cell-type-specific, state-dependent, and synapse-specific reduction in m6A-modified Malat1 disrupts the interaction between Malat1 and DPYSL2 and impairs fear extinction. The consolidation of fear-extinction memory therefore relies on an interaction between m6A-modified Malat1 and select RBPs in the synaptic compartment.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 09, 2022.
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Discovery of synapse-specific RNA N6-methyladenosine readers associated with the consolidation of fear extinction memory
Sachithrani U. Madugalle, Wei-Siang Liau, Qiongyi Zhao, Xiang Li, Hao Gong, Paul R. Marshall, Ambika Periyakaruppiah, Esmi L. Zajackowski, Laura J. Leighton, Haobin Ren, Mason Musgrove, Joshua Davies, Simone Rauch, Chuan He, Bryan C. Dickinson, Lee Fletcher, Barbora Fulopova, Stephen R. Williams, Robert C. Spitale, Timothy W. Bredy
bioRxiv 2022.06.07.495230; doi: https://doi.org/10.1101/2022.06.07.495230
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Discovery of synapse-specific RNA N6-methyladenosine readers associated with the consolidation of fear extinction memory
Sachithrani U. Madugalle, Wei-Siang Liau, Qiongyi Zhao, Xiang Li, Hao Gong, Paul R. Marshall, Ambika Periyakaruppiah, Esmi L. Zajackowski, Laura J. Leighton, Haobin Ren, Mason Musgrove, Joshua Davies, Simone Rauch, Chuan He, Bryan C. Dickinson, Lee Fletcher, Barbora Fulopova, Stephen R. Williams, Robert C. Spitale, Timothy W. Bredy
bioRxiv 2022.06.07.495230; doi: https://doi.org/10.1101/2022.06.07.495230

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