FMRP phosphorylation modulates neuronal translation through YTHDF1

Molecular Cell · 2023 · 82 citations

• Biology
• Cell biology
• Molecular biology

RNA-binding proteins (RBPs) control messenger RNA fate in neurons. Here, we report a mechanism that the stimuli-induced neuronal translation is mediated by phosphorylation of a YTHDF1-binding protein FMRP. Mechanistically, YTHDF1 can condense with ribosomal proteins to promote the translation of its mRNA targets. FMRP regulates this process by sequestering YTHDF1 away from the ribosome; upon neuronal stimulation, FMRP becomes phosphorylated and releases YTHDF1 for translation upregulation. We show that a new small molecule inhibitor of YTHDF1 can reverse fragile X syndrome (FXS) developmental defects associated with FMRP deficiency in an organoid model. Our study thus reveals that FMRP and its phosphorylation are important regulators of activity-dependent translation during neuronal development and stimulation and identifies YTHDF1 as a potential therapeutic target for FXS in which developmental defects caused by FMRP depletion could be reversed through YTHDF1 inhibition.

Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity

Nature · 2023 · 125 citations

• Biology
• Chemistry
• Cell biology

T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.

m6A RNA modifications are measured at single-base resolution across the mammalian transcriptome

Nature Biotechnology · 2022 · 255 citations

• Biology
• Cell biology
• Computational biology

Autophagy of the m6A mRNA demethylase FTO is impaired by low-level arsenic exposure to promote tumorigenesis

Nature Communications · 2021 · 123 citations

• Chemistry
• Cancer research
• Cell biology

A methylation as an epitranscriptomic mechanism to promote arsenic tumorigenicity.

Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response

Nucleic Acids Research · 2021 · 232 citations

• Biology
• Cell biology
• Genetics

Faithful genome integrity maintenance plays an essential role in cell survival. Here, we identify the RNA demethylase ALKBH5 as a key regulator that protects cells from DNA damage and apoptosis during reactive oxygen species (ROS)-induced stress. We find that ROS significantly induces global mRNA N6-methyladenosine (m6A) levels by modulating ALKBH5 post-translational modifications (PTMs), leading to the rapid and efficient induction of thousands of genes involved in a variety of biological processes including DNA damage repair. Mechanistically, ROS promotes ALKBH5 SUMOylation through activating ERK/JNK signaling, leading to inhibition of ALKBH5 m6A demethylase activity by blocking substrate accessibility. Moreover, ERK/JNK/ALKBH5-PTMs/m6A axis is activated by ROS in hematopoietic stem/progenitor cells (HSPCs) in vivo in mice, suggesting a physiological role of this molecular pathway in the maintenance of genome stability in HSPCs. Together, our study uncovers a molecular mechanism involving ALKBH5 PTMs and increased mRNA m6A levels that protect genomic integrity of cells in response to ROS.

m ⁶ A RNA methylation: from mechanisms to therapeutic potential

The EMBO Journal · 2021 · 786 citations

• Biology
• Genetics
• Cell biology

A critical role of nuclear m6A reader YTHDC1 in leukemogenesis by regulating MCM complex–mediated DNA replication

Blood · 2021 · 162 citations

• Biology
• Cell biology
• Cancer research

YTHDC1 has distinct functions as a nuclear N6-methyladenosine (m6A) reader in regulating RNA metabolism. Here we show that YTHDC1 is overexpressed in acute myeloid leukemia (AML) and that it is required for the proliferation and survival of human AML cells. Genetic deletion of Ythdc1 markedly blocks AML development and maintenance as well as self-renewal of leukemia stem cells (LSCs) in vivo in mice. We found that Ythdc1 is also required for normal hematopoiesis and hematopoietic stem and progenitor cell (HSPC) maintenance in vivo. Notably, Ythdc1 haploinsufficiency reduces self-renewal of LSCs but not HSPCs in vivo. YTHDC1 knockdown has a strong inhibitory effect on proliferation of primary AML cells. Mechanistically, YTHDC1 regulates leukemogenesis through MCM4, which is a critical regulator of DNA replication. Our study provides compelling evidence that shows an oncogenic role and a distinct mechanism of YTHDC1 in AML.

An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease

Nature Genetics · 2020 · 369 citations

• Biology
• Genetics
• Computational biology

Genetic analyses support the contribution of mRNA N6-methyladenosine (m6A) modification to human disease heritability

Nature Genetics · 2020 · 195 citations

• Biology
• Genetics

N6-methyladenosine modification enables viral RNA to escape recognition by RNA sensor RIG-I

Nature Microbiology · 2020 · 279 citations

• Biology
• Computational biology
• Virology