| YTHDC1, also known as YT521-B, is a nuclear YTH-domain protein that functions as a selective m6A RNA “reader” and key regulator of pre‑mRNA processing, coupling epitranscriptomic marks to alternative splicing, alternative polyadenylation and nuclear export in a way that shapes gene expression programs across development and disease. The protein contains a C‑terminal YTH domain that specifically recognizes N6‑methyladenosine in target RNAs and an N‑terminal region that interacts with SR‑family splicing factors, enabling it to bridge methylated cis‑elements in exons or 3′UTRs with trans‑acting spliceosomal components. Binding of YTHDC1 to m6A‑containing regions promotes exon inclusion by recruiting SRSF3 to adjacent RNA motifs while simultaneously blocking access of SRSF10, which normally drives exon skipping, so that YTHDC1–m6A complexes favor SRSF3‑like splicing patterns and antagonize SRSF10‑associated exon exclusion. Exons regulated by YTHDC1 overlap with SRSF3 targets and oppose SRSF10-regulated events, and depletion of YTHDC1 disrupts these inclusion/skipping decisions in a manner that can be rescued only by a wild-type m6A‑binding‑competent YTHDC1, demonstrating that m6A recognition is essential for its splicing function. In addition to exon choice, YTHDC1 modulates alternative polyadenylation through interactions with CPSF6, SRSF3 and SRSF7, affecting selection of distal versus proximal poly(A) sites and thereby tuning 3′UTR length and regulatory content in oocyte growth, embryogenesis and other contexts where transcript isoform balance is critical. YTHDC1 also participates in nuclear export of m6A‑marked mRNAs by facilitating binding of SRSF3 and the export receptor NXF1 to these transcripts, positioning it as a coordinator that links methylation status, splice-site usage and export competence along the transcription–processing axis. In limb organogenesis, a specific METTL16–m6A–YTHDC1 axis operates in which YTHDC1 recognizes METTL16-deposited m6A on chromatin-associated RNAs and organizes cotranscriptional splicing of genes essential for cell cycle progression and DNA repair; loss of YTHDC1 or METTL16, but not METTL3, causes severe limb malformations, genome-wide transcription arrest and widespread disruption of developmental gene expression. Chromatin-bound YTHDC1 recruits splicing factors into transcriptional complexes via liquid–liquid phase separation driven by arginine-rich motifs in its C‑terminal region, indicating that YTHDC1 not only reads m6A but also forms dynamic nuclear condensates that concentrate splicing machinery at actively transcribed loci. In myogenic systems, m6A–YTHDC1 orchestrates splicing of mRNAs with key functions in myoblasts and promotes myoblast proliferation and muscle stem cell activity, linking its splicing role to tissue-specific growth and regeneration programs. Across cancers, YTH domain–containing proteins, including YTHDC1, are frequently dysregulated, and altered YTHDC1 expression affects splicing patterns, mRNA export and stability of oncogenes and tumor suppressors; emerging evidence connects YTHDC1-driven changes in isoform usage and RNA metabolism to tumorigenesis in multiple cancer types. |
