Assessing comparative importance of DNA sequence and epigenetic modifications on gene expression using a deep convolutional neural network

Gene expression is regulated at both transcriptional and post-transcriptional levels. DNA sequence and epigenetic modifications are key factors which regulate gene transcription. Understanding their complex interactions and their respective contributions to gene expression regulation remains a challenge in biological studies. We have developed iSEGnet, a framework of deep convolutional neural network to predict mRNA abundance using the information on DNA sequences as well as epigenetic modifications within genes and their cis-regulatory regions. We demonstrate that our framework outperforms other machine learning models in terms of predicting mRNA abundance using transcriptional and epigenetic profiles from six distinct cell lines/types chosen from the ENCODE. The analysis from the learned models also reveals that specific regions around promotors and transcription termination sites are most important for gene expression regulation. Using the method of Integrated Gradients, we identify narrow segments in these regions which are most likely to impact gene expression for a specific epigenetic modification. We further show that these identified segments are enriched in known active regulatory regions by comparing the transcription factor binding sites obtained via ChIP-seq. Moreover, we demonstrate how iSEGnet can uncover potential transcription factors that have regulatory functions in cancer using two cancer multi-omics data.