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YTHDF1-regulated oncogenic translation program offers a therapeutic target for acute myeloid leukemia

ABSTRACT: N6-methyladenosine (m6A), the most abundant modification in mRNAs, has been defined as a crucial modulator in the progression of acute myeloid leukemia (AML), while the detailed mechanism remains elusive. Here we report that YTHDF1, an m6A reader protein, is overexpressed in human AML samples with enrichment in leukemia stem cells (LSCs). Whereas YTHDF1 is dispensable for normal hematopoiesis in mice, depletion of YTHDF1 attenuates self-renewal and proliferation of patient-derived LSCs, and impedes leukemia establishment in immunodeficient mice. Mechanistically, YTHDF1 promotes the translation of diverse m6A-modified oncogene mRNAs particularly cyclin E2. We applied a structure-based virtual screening of FDA-approved drugs and identified tegaserod as a potential YTHDF1 inhibitor. Tegaserod blocks the direct binding of YTHDF1 with m6A-modified mRNAs and inhibits YTHDF1-regulated mRNA translation. Moreover, tegaserod inhibits leukemogenesis in vitro and in mice, phenocopying the loss of YTHDF1. Together, our study defines YTHDF1 as an integral regulator of AML progression at the translational level and identifies tegaserod as a potential therapeutic agent for AML by targeting YTHDF1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184842 | GEO | 2021/09/28

REPOSITORIES: GEO

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N6-methyladenosine Modulates Messenger RNA Translation Efficiency

Project description:N6-methyladenosine (m6A) is the most abundant internal messenger (mRNA) modification in mammalian mRNA. This modification is reversible and non-stoichiometric, which potentially adds an additional layer of variety and dynamic control of mRNA metabolism. The m6A-modified mRNA can be selectively recognized by the YTH family “reader” proteins. The preferential binding of m6A-containing mRNA by YTHDF2 is known to reduce the stability of the target transcripts; however, the exact effects of m6A on translation has yet to be elucidated. Here we show that another m6A reader protein, YTHDF1, promotes ribosome loading of its target transcripts. YTHDF1 forms a complex with translation initiation factors to elevate the translation efficiency of its bound mRNA. In a unified mechanism of translation control through m6A, the YTHDF2-mediated decay controls the lifetime of target transcripts; whereas, the YTHDF1-based translation promotion increases the translation efficiency to ensure effective protein production from relatively short-lived transcripts that are marked by m6A. PAR-CLIP and RIP was used to identify YTHDF1 binding sites followed by ribosome profling and RNA seq to assess the consequences of YTHDF1 siRNA knock-down

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Project description:Obesity, one of the most serious public health issues, is caused by energy imbalance of energy intake and expenditure. N(6)-methyladenosine (m6A) RNA modification has been recently identified as a key regulator of obesity, while the detailed mechanism is elusive. Here, we found that YTH RNA binding protein 1 (YTHDF1), an m6A reader, acts as an essential regulator of white adipose tissue metabolism. The expression of YTHDF1 decreased in adipose tissue of mice fed a high-fat diet. Adipocyte-specific Ythdf1 deficiency exacerbated obesity-induced metabolic defects and inhibited beiging of inguinal white adipose tissue (iWAT) in mice. By contrast, mice with WAT-specific Ythdf1 overexpression were resistant to obesity and showed promotion of beiging. Mechanistically, YTHDF1 regulated the translation of diverse m6A-modified mRNAs. In particular, YTHDF1 facilitated the translation of bone morphogenetic protein 8b (Bmp8b) in an m6A-dependent manner to induce the beiging process. Together, these findings suggested that YTHDF1 may be an attractive therapeutic target for the management of obesity-associated diseases.

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Gene expression and m6A profiling for AGS cells with sh-NC or sh-YTHDF1 [RNA-seq and MeRIP-seq]

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N6-methyladenosine Modulates Messenger RNA Translation Efficiency

2015-06-09 | GSE63591 | GEO

Dynamic O-GlcNAcylation of YTHDF proteins controls translation of m6A-modified mRNA

Project description:N6-methyladenosine (m6A) is the most abundant internal mRNA nucleotide modification in mammals, regulating critical aspects of cell physiology and differentiation. The YTHDF proteins are the primary readers of m6A modifications and exert physiological functions of m6A in the cytosol. Elucidating the regulatory mechanisms of YTHDF proteins is critical to understanding m6A biology. Here, we report a mechanism that protein post-translational modifications control the biological functions of the YTHDF proteins. We find that YTHDF1 and YTHDF3, but not YTHDF2, carry high levels of nutrient-sensing O-GlcNAc modifications. O-GlcNAc modification attenuates the translation promoting function of YTHDF1 and YTHDF3 by blocking their interactions with proteins associated with mRNA translation. We further demonstrate that O-GlcNAc modifications on YTHDF1 and YTHDF2 regulate the assembly, stability, and disassembly of stress granule, facilitating rapid exchange of m6A-modified mRNAs in stress granules for recovery from stress. Therefore, our results discover an important regulatory pathway of YTHDF functions, adding an additional layer of complexity to the post-transcriptional regulation function of mRNA m6A.

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FMRP phosphorylation modulates neuronal translation through YTHDF1

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2023-10-31 | GSE214882 | GEO

m6A-facilitated hippocampal learning and memory through Ythdf1

Project description:N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammalian messenger RNAs (mRNAs). While m6A has been shown to mark groups of mRNAs for coordinated degradation in various physiological processes, the relevance of m6A in affecting translation remains to be determined in intact biological systems in vivo. Here we show that, through its reader protein Ythdf1, m6A promotes a pulse of protein synthesis of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory processes. Mice with genetic deletion of the Ythdf1 gene (Ythdf1-/-) exhibit learning and memory defects, as well as impaired hippocampal synaptic transmission and long-term potentiation (LTP). Selective re-expression of Ythdf1 in the hippocampus of adult Ythdf1-/- mice fully rescues the behavioral and synaptic defects, while hippocampus-specific knockdown of Ythdf1 or Mettl3, the catalytic component of m6A methyltransferase complex, recapitulates the hippocampal deficiency in adult mice. At the molecular level, transcriptome-wide mapping of m6A sites and RNA binding sites of Ythdf1 on hippocampal mRNAs using crosslinking immunoprecipitation followed by high-throughput sequencing (CLIP-seq) uncovered key neuronal genes, including those involved in synaptic transmission and long-term potentiation. Nascent protein labelling and tether reporter assays in cultured hippocampal neurons revealed that Ythdf1 is critical for initiating a pulse of protein synthesis of target transcripts in a neuronal-stimulus-dependent manner. Collectively, our results uncover a pathway of mRNA m6A methylation in learning and memory, which is mediated through Ythdf1 in response to stimuli.

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