Predicting the impact of sequence motifs on gene regulation using single-cell data

Abstract

BackgroundBinding of transcription factors (TFs) at proximal promoters and distal enhancers is central to gene regulation. Yet, identification of TF binding sites, also known as regulatory motifs, and quantification of their impact on gene expression remains challenging. ResultsHere we infer putative regulatory motifs along with their cell type-specific importance using a convolutional neural network trained on single-cell data. Comparison of the importance score to expression levels across cells allows us to identify the TFs most likely to be binding at a given motif. Using multiple mouse tissues we obtain a model with cell type resolution which explains 29% of the variance in gene expression. Finally, by applying scover to distal enhancers identified using scATAC-seq from the mouse cerebral cortex we characterize changes in distal regulatory motifs during development. ConclusionsIt is possible to identify regulatory motifs as well as their importance from single-cell data using a neural network model where all of the parameters and outputs are easily interpretable to the user.