Genomic language model for predicting enhancers and their allele-specific activity in the human genome.

Abstract

MOTIVATION Predicting and deciphering the regulatory logic of enhancers remains a significant challenge due to their complex sequence features and the absence of consistent genetic or epigenetic signatures that distinguish them from other genomic regions. Existing machine learning methods capture nucleotide composition but often fail to model sequence context effectively. RESULTS We present DNABERT-Enhancer, a novel enhancer prediction method, by applying DNABERT pre-trained language model on the human genome. Using ENCODE registry of candidate cis-regulatory elements (cCREs), we curated a benchmark dataset, consisting of 21,926 enhancers of 201 bp length and 46,159 enhancers of 350 bp length, as positive instances. The best fine-tuned model achieved 88.05% accuracy and a Matthews correlation coefficient of 76% on an independent dataset. Genome-wide application identified 1,684,595 enhancer regions covering 26.65% of the human genome. By performing integrative analyses with DNABERT-based transcription factor models, we identify 2,681 statistically significant loss-of-function and 1,917 gain-of-function enhancer variants, which respectively alter the function of 1,623 and 1,247 ENCODE-cCRE enhancers. Similarly, we identify 4,057 candidate de novo enhancers, created by 5,464 gain-of-function variants. These genome-wide enhancer annotations and candidate genetic variants predicted by DNABERT-Enhancer provide valuable resources for genome interpretation in functional and clinical genomics studies. AVAILABILITY DNABERT-Enhancer is freely available at https://github.com/DavuluriLab/DNABERT-Enhancer; Trained model predictions can be explored interactively via the web application at https://dnabert-enhancer-datarepo.streamlit.app/. The fine-tuned models are archived and citable through Zenodo (https://doi.org/10.5281/zenodo.19157566). SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.