N⁶-methyladenosine (m⁶A) is the most abundant internal modification of eukaryotic messenger RNA (mRNA) and plays critical roles in RNA biology. The function of this modification is mediated by m⁶A-selective ‘reader’ proteins of the YTH family, which incorporate m⁶A-modified mRNAs into pathways of RNA metabolism. Here, we show that the m⁶A-binding protein YTHDC1 mediates export of methylated mRNA from the nucleus to the cytoplasm in HeLa cells. Knockdown of YTHDC1 results in an extended residence time for nuclear m⁶A-containing mRNA, with an accumulation of transcripts in the nucleus and accompanying depletion within the cytoplasm. YTHDC1 interacts with the splicing factor and nuclear export adaptor protein SRSF3, and facilitates RNA binding to both SRSF3 and NXF1. This role for YTHDC1 expands the potential utility of chemical modification of mRNA, and supports an emerging paradigm of m⁶A as a distinct biochemical entity for selective processing and metabolism of mammalian mRNAs.

Cancer-testis (CT) genes represent the similarity between the processes of spermatogenesis and tumorigenesis. It is possible that their selective expression pattern can help identify driver genes in cancer. In this study, we integrate transcriptomics data from multiple databases and systematically identify 876 new CT genes in 19 cancer types. We explore their relationship with testis-specific regulatory elements. We propose that extremely highly expressed CT genes (EECTGs) are potential drivers activated through epigenetic mechanisms. We find mutually exclusive associations between EECTGs and somatic mutations in mutated genes, such as PIK3CA in breast cancer. We also provide evidence that promoter demethylation and close non-coding RNAs (namely, CT-ncRNAs) may be two mechanisms to reactivate EECTG gene expression. We show that the meiosis-related EECTG (MEIOB) and its nearby CT-ncRNA have a role in tumorigenesis in lung adenocarcinoma. Our findings provide methods for identifying epigenetic-driver genes of cancer, which could serve as targets of future cancer therapies.