A New Paradigm for Genome-wide DNA Methylation Prediction Without Methylation Input

DNA methylation (DNAm) is a key epigenetic modification that regulates gene expression and is pivotal in development and disease. However, profiling DNAm at genome scale is challenging: of $\textasciitilde$28 million CpG sites in the human genome, only about 1–3% are typically assayed in common datasets due to technological limitations and cost. Recent deep learning approaches, including masking-based generative Transformer models, have shown promise in capturing DNAm–gene expression relationships, but they rely on partially observed DNAm values for unmeasured CpGs and cannot be applied to completely unmeasured samples. To overcome this barrier, we introduce MethylProphet, a gene-guided, context-aware Transformer model for whole-genome DNAm inference without any measured DNAm input. MethylProphet compresses comprehensive gene expression profiles ($\textasciitilde$25K genes) through an efficient bottleneck multilayer perceptron, and encodes local CpG sequence context with a specialized DNA tokenizer. These representations are integrated by a Transformer encoder to predict site-specific methylation levels. Trained on large-scale pan-tissue whole-genome bisulfite sequencing data from ENCODE (1.6 billion CpG–sample pairs, $\textasciitilde$322 billion tokens), MethylProphet demonstrates strong performance in hold-out evaluations, accurately inferring DNAm at unmeasured CpGs and generalizing to unseen samples. Furthermore, application to TCGA pan-cancer data (chromosome 1, 9,194 samples; $\textasciitilde$450 million training pairs, 91 billion tokens) highlights its potential for pan-cancer whole-genome methylome imputation. MethylProphet offers a powerful and scalable foundation model for epigenetics, providing high-resolution methylation landscape reconstruction and advancing both biological research and precision medicine.