m<sup>6</sup>A facilitates hippocampus‐dependent learning and memory through Ythdf1

Shi, Hailing; Zhang, Xuliang; Lu, Zongyang; Liu, Yajing; Weng, Yi‐Lan; Lu, Zhike; Li, Jianan; Hao, Piliang; Zhang, Yu; Delgado, Jary Y.; Patel, Meera J.; Cao, Xiaohua; Huang, Xingxu; Su, Yijing; Ming, Guo‐li; Zhuang, Xiaoxi; Song, Hongjun; He, Chuan; Zhou, Tao

doi:10.1096/fasebj.2018.32.1_supplement.787.6

Cited by 12 publications

(11 citation statements)

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“…Different from the complicated regulation in mRNA translation of YTHDF2 and YTHDF3, 14,36 YTHDF1 is frequently reported to enhance the translation of its targeted mRNAs. 37,38 In accordance with the previous results, 18,26 we found that YTHDF1 can promote the translation of EGFR mRNA and modulates the activities of corresponding downstream pathways that impact the ICC progression, supporting the reported basic pattern of YTHDF1 in modulating cancer biology. To further dissect the mechanisms of YTHDF1 in ICC, we have mutated the YTH domain and found that overexpression of mutant YTHDF1 does not facilitate the malignant abilities of ICC cells.…”

Section: Discussionsupporting

confidence: 90%

YTHDF1 promotes intrahepatic cholangiocarcinoma progression via regulating EGFR mRNA translation

Huang

Zhu

Wang

et al. 2022

J of Gastro and Hepatol

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Background and Aim: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive disease with the underlying mechanisms poorly understood. YTHDF1, an N 6methyladenosine (m 6 A) reader protein, has important physiological functions in regulation of tumor development. However, the effect of YTHDF1 on ICC progression remains unknown yet. Methods: The expression level of YTHDF1 in human ICC tissue was examined in The Cancer Genome Atlas database and our cohort. The role of YTHDF1 was detected using two human ICC cell lines in vitro. An ICC tumorigenesis mouse model was established via hydrodynamic transfection of AKT/YAP plasmids. m 6 A sequencing, RNA immunoprecipitation sequencing, and RNA sequencing were carried out to explore the mechanism of YTHDF1 modulating ICC progression.Results: Here, we find that YTHDF1 is upregulated in ICC and associated with shorter survival of ICC patients. Depletion of YTHDF1 inhibits cell proliferation, migration, and invasion, while overexpression of wild-type YTHDF1, but not m 6 A reader domain mutant YTHDF1, significantly enhances tumor cell growth and aggressive abilities in vitro. Moreover, overexpression of YTHDF1 promotes the AKT/YAP transfection-induced orthotopic ICC tumorigenesis and progression in vivo. Mechanistically, we identify that YTHDF1 regulates the translation of epidermal growth factor receptor (EGFR) mRNA via binding m 6 A sites in the 30-UTR of EGFR transcript, thus leading to aberrant activities of downstream signal pathways that impact tumor progression. Conclusions: Our data uncover the oncogenic function and m 6 A reader-dependent mechanism of YTHDF1 in regulation of ICC progression. Restricting abnormal oncogenic mRNA translation by targeting YTHDF1 may be a novel and promising strategy for ICC treatment.

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Section: Discussionsupporting

confidence: 90%

YTHDF1 promotes intrahepatic cholangiocarcinoma progression via regulating EGFR mRNA translation

Huang

Zhu

Wang

et al. 2022

J of Gastro and Hepatol

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“…Moreover, m 6 A reader proteins, including the Ythdf and Ythdc family members, specifically recognize m 6 A modification to govern the processing and translation of m 6 A-modified mRNAs. Intriguingly, the emerging biological functions affected by m 6 A manipulation include stem cell commitment, 2 stress response, 3 neuronal functions, 4 and memory formation, 5 highlighting its crucial role in brain development and disorders such as major depression.…”

Section: Introductionmentioning

confidence: 99%

Mettl3‐mediated m⁶A modification of Lrp2 facilitates neurogenesis through Ythdc2 and elicits antidepressant‐like effects

et al. 2022

The FASEB Journal

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N6‐methyladenosine (m6A) is the most abundant mRNA modification affecting diverse biological processes. However, the functions and precise mechanisms of m6A signaling in adult hippocampal neurogenesis and neurogenesis‐related depression remain largely enigmatic. We found that depletion of Mettl3 or Mettl14 in neural stem cells (NSCs) dramatically reduced m6A abundance, proliferation, and neuronal genesis, coupled with enhanced glial differentiation. Conversely, overexpressing Mettl3 promoted proliferation and neuronal differentiation. Mechanistically, the m6A modification of Lrp2 mRNA by Mettl3 enhanced its stability and translation efficiency relying on the reader protein Ythdc2, which in turn promoted neurogenesis. Importantly, mice lacking Mettl3 manifested reduced hippocampal neurogenesis, which could contribute to spatial memory decline, and depression‐like behaviors. We found that these defective behaviors were notably reversed by Lrp2 overexpression. Moreover, Mettl3 overexpression in the hippocampus of depressive mice rescues behavioral defects. Our findings uncover the biological role of m6A modification in Lrp2‐mediated neurogenesis via m6A‐binding protein Ythdc2, and propose a rationale that targeting Mettl3‐Ythdc2‐Lrp2 axis regulation of neurogenesis might serve as a promising antidepressant strategy.

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“…By contrast, Ythdf1, the other m 6 A reader, promotes translation of target transcripts (Wang et al . 2015; Shi et al . 2018; Shi et al .…”

Section: Resultsmentioning

confidence: 99%

Mettl3-mediated m⁶A modification of Fgf16 restricts cardiomyocyte proliferation during heart regeneration

Jiang

Chen

et al. 2022

Preprint

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Cardiovascular disease is the leading cause of death worldwide due to the inability of adult heart to regenerate after injury. N6-methyladenosine (m6A) methylation catalyzed by the enzyme methyltransferase-like 3 (Mettl3) plays important roles in various physiological and pathological bioprocesses. However, the role of m6A in heart regeneration remains largely unclear. To study m6A function in heart regeneration, we modulated Mettl3 expression in vitro and in vivo. Knockdown of Mettl3 significantly increased the proliferation of cardiomyocytes and accelerated heart regeneration following heart injury in neonatal and adult mice. However, Mettl3 overexpression decreased cardiomyocyte proliferation and suppressed heart regeneration in postnatal mice. Conjoint analysis of methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq identified Fgf16 as a downstream target of Mettl3-mediated m6A modification during postnatal heart regeneration. RIPqPCR and luciferase reporter assays revealed that Mettl3 negatively regulates Fgf16 mRNA expression in an m6AYthdf2-dependent manner. The silencing of Fgf16 suppressed the proliferation of cardiomyocytes. However, the overexpression of ΔFgf16, in which the m6A consensus sequence was mutated, significantly increased cardiomyocyte proliferation and accelerated heart regeneration in postnatal mice compared with wild-type Fgf16. Our data demonstrate that Mettl3 post-transcriptionally reduces Fgf16 mRNA levels through an m6A-Ythdf2-dependen pathway, thereby controlling cardiomyocyte proliferation and heart regeneration.

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m⁶A facilitates hippocampus‐dependent learning and memory through Ythdf1

Cited by 12 publications

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YTHDF1 promotes intrahepatic cholangiocarcinoma progression via regulating EGFR mRNA translation

YTHDF1 promotes intrahepatic cholangiocarcinoma progression via regulating EGFR mRNA translation

Mettl3‐mediated m⁶A modification of Lrp2 facilitates neurogenesis through Ythdc2 and elicits antidepressant‐like effects

Mettl3-mediated m⁶A modification of Fgf16 restricts cardiomyocyte proliferation during heart regeneration

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m6A facilitates hippocampus‐dependent learning and memory through Ythdf1

Cited by 12 publications

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YTHDF1 promotes intrahepatic cholangiocarcinoma progression via regulating EGFR mRNA translation

YTHDF1 promotes intrahepatic cholangiocarcinoma progression via regulating EGFR mRNA translation

Mettl3‐mediated m6A modification of Lrp2 facilitates neurogenesis through Ythdc2 and elicits antidepressant‐like effects

Mettl3-mediated m6A modification of Fgf16 restricts cardiomyocyte proliferation during heart regeneration

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m⁶A facilitates hippocampus‐dependent learning and memory through Ythdf1

Mettl3‐mediated m⁶A modification of Lrp2 facilitates neurogenesis through Ythdc2 and elicits antidepressant‐like effects

Mettl3-mediated m⁶A modification of Fgf16 restricts cardiomyocyte proliferation during heart regeneration