m6A facilitates hippocampus-dependent learning and memory through YTHDF1

Abstract

Summary N 6 -methyladenosine (m 6 A), the most prevalent internal RNA modification on mammalian messenger RNAs (mRNAs), regulates fates and functions of modified transcripts through m 6 A-specific binding proteins 1 – 5 . m 6 A is abundant in the nervous system and modulates various neural functions 6 – 11 . While m 6 A marks groups of mRNAs for coordinated degradation in various physiological processes 12 – 15 , the relevance of m 6 A in mRNA translation remains largely unknown in vivo . Here we show that, through its binding protein Ythdf1, m 6 A promotes protein synthesis of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory. Mice with genetic deletion of Ythdf1 ( Ythdf1 -KO) exhibit learning and memory defects as well as impaired hippocampal synaptic transmission and long-term potentiation. Ythdf1 re-expression in the hippocampus of adult Ythdf1 -KO mice rescues behavioral and synaptic defects, while hippocampus-specific acute knockdown of Ythdf1 or Mettl3 , the catalytic component of m 6 A methyltransferase complex, recapitulates the hippocampal deficiency. Transcriptome-wide mapping of Ythdf1 binding sites and m 6 A sites on hippocampal mRNAs uncovered key neuronal genes. Nascent protein labeling and tether reporter assays in hippocampal neurons revealed that Ythdf1 enhances protein synthesis in a neuronal-stimulus-dependent manner. Collectively, our results uncover a pathway of mRNA m 6 A methylation in learning and memory, which is mediated through Ythdf1 in response to stimuli.

Linking m 6 A to Wnt signaling

“…Consistent with this notion, YTHDF1 knockdown decreased the translational efficiency of a subgroup of m 6 A-marked target mRNAs including the key components in Wnt/b-catenin signaling pathway [1]. 6 A in stem cell biology. It is intriguing that YTHDF1 is dispensable for physiological intestinal development, but becomes essential during intestinal regeneration.…”

“…Despite the well-established role of b-catenin in Wnt signaling, additional layers of regulatory signals remain poorly understood. In this issue, Han et al [1] describe a previously unappreciated mechanism required for the amplification of Wnt signaling during ISC homeostasis, which involves YTHDF1-and m 6 A-dependent translational control of the key transcriptional activator TCF4.…”

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

“…Indeed, m6A is one of the major modifications of RNA that regulates the processing, translation and decay of RNA, which plays a key role in RNA metabolism and function . Furthermore, m6A, which is mainly catalysed by METTL3, regulates RNA stability mainly through m6A‐specific binding proteins which in turn determines cellular fate and function . In particular, N 6 ‐methyladenosine (m 6 A) has been shown recently to play essential roles in various bioprocesses .…”

Different DNA methylation profile is demonstrated in paracoccidioidomycosis patients without oral lesions

“…YTHDF1 is a member of YTH domain family proteins, which has been described acting for the selective binding of N 6 ‐methyladenosine (m 6 A) in mRNA . Among its physiological roles, YTHDF1 enables translation of m 6 A‐methylated neuronal mRNAs in reaction to neuronal stimulus, which aids to learning and memory . On the other hand, protein expression of YTHDF1 is upregulated in hepatocellular carcinoma (HCC), being associated with tumour cell cycle, base excision repair, DNA replication, RNA splicing and RNA degradation .…”

“…42 Among its physiological roles, YTHDF1 enables translation of m 6 A-methylated neuronal mRNAs in reaction to neuronal stimulus, which aids to learning and memory. 43 On the other hand, protein expression of YTHDF1 is upregulated in hepatocellular carcinoma (HCC), being associated with tumour cell cycle, base excision repair, DNA replication, RNA splicing and RNA degradation. 44,45 The patterns of DNA methylation are altered in response to changes in diet and also to environmental exposure.…”