An Energy Model for Recognizing the Histone Modification Signal Levels in lncRNA Promoter Regions of HCC Based on Molecular Structure

In hepatocellular carcinoma (HCC), aberrant histone modifications are linked to the dysregulation of long non-coding RNA (lncRNA) expression. Although existing computational models can accurately predict some associations, they lack deep physical interpretability. We constructed an energy model based on the physical principle that energy determines molecular structure. Total DNA segment energy was calculated by summing adjacent trinucleotide interaction energies and applied to analyze 11 key histone modifications in HCC, specifically within lncRNA promoter regions where modification signals were increased or decreased. Finally, ten-fold cross-validation revealed that significant energy differences between sequences with increased and decreased histone signals enable excellent classification performance. These results indicted a strong correlation between the total energy of local DNA structures and histone modification signal. Furthermore, introducing longer k-mers led to computational redundancy without a consistent improvement, confirming that the trinucleotide model most effectively acquires the local DNA structural changes associated with histone modification levels. Our model can effectively distinguish DNA sequences associated with different histone modification levels from a physical energy perspective. This model serves as an interpretable tool for epigenetic research while providing a new understanding a new perspective for understanding the dysregulation of lncRNA expression in HCC.