Integrating distal and proximal information to predict gene expression via a densely connected convolutional neural network

Motivation: Interactions among cis-regulatory elements such as enhancers and promoters are main driving forces shaping context-specific chromatin structure and gene expression. Although there have been computational methods for predicting gene expression from genomic and epigenomic information, most of them neglect long-range enhancer-promoter interactions, due to the difficulty in precisely linking regulatory enhancers to target genes. Recently, HiChIP, a novel high-throughput experimental approach, has generated comprehensive data on high-resolution interactions between promoters and distal enhancers. Moreover, plenty of studies suggest that deep learning achieves state-of-the-art performance in epigenomic signal prediction, and thus promoting the understanding of regulatory elements. In consideration of these two factors, we integrate proximal promoter sequences and HiChIP distal enhancer-promoter interactions to accurately predict gene expression. Results: We propose DeepExpression, a densely connected convolutional neural network, to predict gene expression using both promoter sequences and enhancer-promoter interactions. We demonstrate that our model consistently outperforms baseline methods, not only in the classification of binary gene expression status but also in regression of continuous gene expression levels, in both cross-validation experiments and cross-cell line predictions. We show that the sequential promoter information is more informative than the experimental enhancer information; meanwhile, the enhancer-promoter interactions within +/- 100 kbp around the TSS of a gene are most beneficial. We finally visualize motifs in both promoter and enhancer regions and show the match of identified sequence signatures with known motifs. We expect to see a wide spectrum of applications using HiChIP data in deciphering the mechanism of gene regulation.