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

AO_SCPLOWBSTRACTC_SCPLOWDNA 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 [~]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 ([~]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, [~]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; [~]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.