DNABERT-2: Fine-Tuning a Genomic Language Model for Colorectal Gene Enhancer Classification

Abstract

Gene enhancers control when and where genes switch on, yet their sequence diversity and tissue specificity make them hard to pinpoint in colorectal cancer. We take a sequence-only route and fine-tune DNABERT-2, a transformer genomic language model that uses byte-pair encoding to learn variable-length tokens from DNA. Using assays curated via the Johnston Cancer Research Centre at Queen's University Belfast, we assembled a balanced corpus of 2.34 million 1 kb enhancer sequences, applied summit-centered extraction and rigorous de-duplication including reverse-complement collapse, and split the data stratified by class. With a 4096-term vocabulary and a 232-token context chosen empirically, the DNABERT-2-117M classifier was trained with Optuna-tuned hyperparameters and evaluated on 350742 held-out sequences. The model reached PR-AUC 0.759, ROC-AUC 0.743, and best F1 0.704 at an optimized threshold (0.359), with recall 0.835 and precision 0.609. Against a CNN-based EnhancerNet trained on the same data, DNABERT-2 delivered stronger threshold-independent ranking and higher recall, although point accuracy was lower. To our knowledge, this is the first study to apply a second-generation genomic language model with BPE tokenization to enhancer classification in colorectal cancer, demonstrating the feasibility of capturing tumor-associated regulatory signals directly from DNA sequence alone. Overall, our results show that transformer-based genomic models can move beyond motif-level encodings toward holistic classification of regulatory elements, offering a novel path for cancer genomics. Next steps will focus on improving precision, exploring hybrid CNN-transformer designs, and validating across independent datasets to strengthen real-world utility.