The m6A epitranscriptome: transcriptome plasticity in brain development and function

Livneh, Ido; Moshitch-Moshkovitz, Sharon; Amariglio, Ninette; Rechavi, Gideon; Dominissini, Dan

doi:10.1038/s41583-019-0244-z

Cited by 238 publications

(224 citation statements)

References 131 publications

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“…Mutants in writer (mettl3 and mettl14), reader (primarily ythdf1), and eraser (FTO) factors have collectively been shown to exhibit aberrant neurogenesis and/or differentiation (Wang et al, 2018a;Yoon et al, 2017) Ma et al, 2018;Wang et al, 2018b;Weng et al, 2018), which impact neural function and organismal behavior (Hess et al, 2013;Koranda et al, 2018;Widagdo et al, 2016). Overall, these observations may be taken as indications for the general usage of m 6 A to guide cell fate transitions along cell lineages, but may also reflect some heightened requirements in neurons, perhaps owing to their unique architectures or regulatory needs (Du et al, 2019;Livneh et al, 2019;Widagdo and Anggono, 2018).…”

Section: Introductionmentioning

confidence: 99%

A neural m⁶A/YTHDF pathway is required for learning and memory inDrosophila

Kan

Ott

Joseph

et al. 2020

Preprint

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The roles of epitranscriptomic modifications in mRNA regulation have recently received substantial attention, with appreciation growing for their phenotypically selective impacts within the animal. We adopted Drosophila melanogaster as a model system to study m 6 A, the most abundant internal modification of mRNA. Here, we report proteomic and functional analyses of fly m 6 A-binding proteins, confirming nuclear (YTHDC) and cytoplasmic (YTHDF) YTH domain proteins as the major m 6 A binders. Since all core m 6 A pathway mutants are viable, we assessed in vivo requirements of the m 6 A pathway in cognitive processes. Assays of short term memory revealed an age-dependent requirement of m 6 A writers working via YTHDF, but not YTHDC, comprising the first phenotypes assigned to Drosophila mutants of the cytoplasmic m 6 A reader.These factors promote memory via neural-autonomous activities, and are required in the mushroom body, the center for associative learning. To inform their basis, we mapped m 6 A from wild-type and mettl3 null mutant heads, allowing robust discrimination of Mettl3-dependent m 6 A sites. In contrast to mammalian m 6 A, which is predominant in 3' UTRs, Drosophila m 6 A is highly enriched in 5' UTRs and occurs in an adenosine-rich context. Genomic analyses demonstrate that Drosophila m 6 A does not directionally affect RNA stability, but is preferentially deposited on genes with low translational efficiency. However, functional tests indicate a role for m 6 A in translational activation, since we observe reduced nascent protein synthesis in mettl3-KO cells.Finally, we show that ectopic YTHDF can increase m 6 A target reporter output in an m 6 A-binding dependent manner, and that this activity is required for in vivo neural function of YTHDF in memory. Altogether, we provide the first tissue-specific m 6 A maps in this model organism and reveal selective behavioral and translational defects for m 6 A/YTHDF mutants.

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Section: Introductionmentioning

confidence: 99%

A neural m⁶A/YTHDF pathway is required for learning and memory inDrosophila

Kan

Ott

Joseph

et al. 2020

Preprint

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“…Brain is one of the organs with the most abundant of m 6 A modification [118,119]. m 6 A regulatory proteins are implicated in the cerebral cortex and synaptic function, axonal regeneration, self-renewal of neural stem cells and cerebellar development [118][119][120][121][122]. m 6 A methylation effectuates the region-specific gene regulation in the mouse brain [118].…”

Section: A In Nervous Systemmentioning

confidence: 99%

Function and evolution of RNA N6-methyladenosine modification

2020

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N6-methyladenosine (m 6 A) is identified as the most prevalent and abundant internal RNA modification, especially within eukaryotic mRNAs, which has attracted much attention in recent years since its importance for regulating gene expression and deciding cell fate. m 6 A modification is installed by RNA methyltransferases METTL3, METTL14 and WTAP (Writers), removed by the demethylases FTO and ALKBH5 (Erasers) and recognized by m 6 A binding proteins, such as YT521-B homology YTH domain-containing proteins (Readers). Accumulating evidence shows that m 6 A RNA methylation participates in almost all aspects of RNA processing, implying an association with important bioprocesses. In this review, we mainly summarize and discuss the functional relevance and importance of m 6 A modification in cellular processes.

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“…Increasing evidence suggests a central role of m 6 A during nervous system development and functions (Angelova et al, 2018;Du et al, 2019;Jung and Goldman, 2018;Li et al, 2019;Livneh et al, 2020;Widagdo and Anggono, 2018). m 6 A is present at particularly high levels in the nervous system of different model animals (Lence et al, 2016;Meyer et al, 2012), and these levels can vary following behavioral stimuli or sensory experience (Engel et al, 2018;Koranda et al, 2018;Widagdo et al, 2016;Yoon et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Discussion m 6 A on mRNA is emerging as a key modulator of nervous system biology (for recent review see (Livneh et al, 2020)). Despite the increasing amount of data associating m 6 A function to brain development, neuronal differentiation, regeneration and synaptic function, the molecular mechanisms underlying these functions remain largely incomplete.…”

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confidence: 99%

The m⁶A reader Ythdf restricts axonal growth inDrosophilathrough target selection modulation of the Fragile X mental retardation protein

Soldano

Worpenberg

Paolantoni

et al. 2020

Preprint

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N6-methyladenosine (m6A) regulates a variety of physiological processes through modulation of RNA metabolism. The modification is particularly enriched in the nervous system of several species, and its dysregulation has been associated with neurodevelopmental defects and neural dysfunctions. In Drosophila, loss of m6A alters fly behavior albeit the underlying mechanism and the role of m6A during nervous system development have remained elusive. Here we find that impairment of the m6A pathway leads to axonal overgrowth and misguidance at larval neuromuscular junctions as well as in the adult mushroom bodies. We identify Ythdf as the main m6A reader in the nervous system being required for limiting axonal growth. Mechanistically, we show that Ythdf directly interacts with Fragile X mental retardation protein to inhibit the translation of key transcripts involved in axonal growth regulation. Altogether, this study demonstrates that the m6A pathway controls development of the nervous system by modulating Fmr1 target selection.

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The m6A epitranscriptome: transcriptome plasticity in brain development and function

Cited by 238 publications

References 131 publications

A neural m⁶A/YTHDF pathway is required for learning and memory inDrosophila

A neural m⁶A/YTHDF pathway is required for learning and memory inDrosophila

Function and evolution of RNA N6-methyladenosine modification

The m⁶A reader Ythdf restricts axonal growth inDrosophilathrough target selection modulation of the Fragile X mental retardation protein

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The m6A epitranscriptome: transcriptome plasticity in brain development and function

Cited by 238 publications

References 131 publications

A neural m6A/YTHDF pathway is required for learning and memory inDrosophila

A neural m6A/YTHDF pathway is required for learning and memory inDrosophila

Function and evolution of RNA N6-methyladenosine modification

The m6A reader Ythdf restricts axonal growth inDrosophilathrough target selection modulation of the Fragile X mental retardation protein

Contact Info

Product

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A neural m⁶A/YTHDF pathway is required for learning and memory inDrosophila

A neural m⁶A/YTHDF pathway is required for learning and memory inDrosophila

The m⁶A reader Ythdf restricts axonal growth inDrosophilathrough target selection modulation of the Fragile X mental retardation protein