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YTHDs in Epigenetics and Disease

The YT521-B Homology Domain (YTHD) pathway encompasses the cellular signaling and regulatory processes mediated by YTH-domain proteins. It is a central component of the epitranscriptomic N6-methyladenosine (m6A) RNA modification system, where YTH-domain proteins function as “readers” that recognize m6A-modified RNA and regulate mRNA stability, splicing, translation, and decay. N6-methyladenosine is the most abundant internal modification in eukaryotic mRNA, interpreted primarily by proteins such as YTHDF1–3 and YTHDC1–2. Dysregulation of these proteins has been linked to cancer, metabolic disorders, infertility, and neurological diseases.

 
Protein / Family Epigenetic Function Disease Association Key Publications Key Products
YTHDF Cytoplasmic m6A reader, translation efficiency, degradation of RNA, RNA splicing and nuclear export, RNA stability during meiosis. Various cancers (Colorectal cancer, hepatocellular carcinoma, gastric cancer, myeloid leukemia), immuno disorders, infertility and reproductive disorders. Zhang et al., Bioorg. Med. Chem. 2023
METTL3 Core catalytic enzyme of the m6A methyltransferase “writer” complex that installs m6A marks recognized by YTH proteins. Acute myeloid leukemia, lung cancer, liver cancer. Wang et al., Nature Communications. 2021
METTL14 Structural partner of METTL3 in the m6A writer complex. Stabilizes RNA substrate recognition for m6A methylation. Leukemia, hepatocellular carcinoma. Wang et al., Nature Communications. 2021
WTAP Regulatory component of the m6A writer complex that recruits METTL3/METTL14 to RNA. Leukemia, renal cancers. Cao et al., AM J Cancer Res. 2025
FTO m6A demethylase (“eraser”) that removes methyl groups from RNA. Obesity, acute myeloid leukemia, metabolic disorders. Chen et al., IMR Press. 2022
ALKBH5 m6A eraser that demethylates mRNA in the nucleus. Glioblastoma, breast cancer, infertility. Zhang et al., Int. J. Mol. Med. 2024
EIF3 Translation initiation factor recruited by YTHDF1 to enhance translation. Multiple cancers. Ren et al., Biomarker Research. 2023
IGF2BP1 m6A reader family that stabilizes methylated transcripts. Protects m6A-modified mRNAs from degradation. Hepatocellular carcinoma, colorectal cancer. Pan et al., Oncology Reports. 2024
HNRNPA2B1 Indirect m6A reader regulating RNA processing and miRNA maturation. Neurodegeneration, cancer. Chen et al., IMR Press. 2022

 

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