Interpretable prediction of mRNA abundance from promoter sequence using contextual regression models

While machine learning models have been successfully applied to predicting gene expression from promoter sequences, it remains a great challenge to derive intuitive interpretation of the model and reveal DNA motif grammar such as motif cooperation and distance constraint between motif sites. Previous interpretation approaches are often time-consuming or have difficulty to learn the combinatory rules. In this work, we designed interpretable neural network models to predict the mRNA expression levels from DNA sequences. By applying the Contextual Regression framework we developed, we extracted weighted features to cluster samples into different groups, which have different gene expression levels. We performed motif analysis in each cluster and found motifs with active or repressive regulation on gene expression. By comparing the co-occurrence locations of discovered motifs, we also uncovered multiple grammars of motif combination including communities of cooperative motifs and distance constraints between motif pairs. These results revealed new insights of the regulatory architecture of promoter sequences.