N
6
-methyladenosine (m
6
A) is the most abundant internal modification on mammalian messenger RNA (mRNA). It is installed by a writer complex and can be reversed by erasers such as the fat mass and obesity-associated protein (FTO). Despite extensive research, the primary physiological substrates of FTO in mammalian tissues and development remain elusive. Here, we show that FTO mediates m
6
A demethylation of long-interspersed element-1 (LINE1) RNA in mouse embryonic stem cells (mESCs), regulating LINE1 RNA abundance and the local chromatin state, which in turn modulates transcription of LINE1-containing genes. FTO-mediated LINE1 RNA m
6
A demethylation also plays regulatory roles in shaping chromatin state and gene expression during mouse oocyte and embryonic development. Our results suggest broad effects of LINE1 RNA m
6
A demethylation by FTO in mammals.
N
6
-methyladenosine (m
6
A)
, catalyzed by the methyltransferase complex consisting of
Mettl3
and Mettl14, is the most abundant RNA modification in mRNAs and participates in diverse biological processes. However, the roles and precise mechanisms of m
6
A modification in regulating
neuronal development
and adult
neurogenesis
remain unclear. Here, we examined the function of Mettl3, the key component of the complex, in neuronal development and adult neurogenesis of mice. We found that the depletion of
Mettl3
significantly reduced m
6
A levels in adult neural stem cells (aNSCs) and inhibited the proliferation of aNSCs.
Mettl3
depletion not only inhibited neuronal development and skewed the differentiation of aNSCs more toward glial lineage, but also affected the morphological maturation of newborn neurons in the adult brain. m
6
A immunoprecipitation combined with deep sequencing (MeRIP-seq) revealed that m
6
A was predominantly enriched in transcripts related to neurogenesis and neuronal development. Mechanistically, m
6
A was present on the transcripts of histone methyltransferase
Ezh2
, and its reduction upon
Mettl3
knockdown decreased both Ezh2 protein expression and consequent H3K27me3 levels. The defects of neurogenesis and neuronal development induced by
Mettl3
depletion could be rescued by
Ezh2
overexpression. Collectively, our results uncover a crosstalk between RNA and histone modifications and indicate that Mettl3-mediated m
6
A modification plays an important role in regulating neurogenesis and neuronal development through modulating
Ezh2
.
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