Sequence based prediction of cell type specific microRNA binding and mRNA degradation for therapeutic discovery

MicroRNAs and RNA binding proteins are crucial elements of post-transcriptional gene regulation, which governs the fate of mRNA molecules in the cell. However, the landscape of these regulatory interactions, particularly across different mammalian cell types, remains underexplored. We describe REPRESS, a deep learning model that predicts cell-type-specific microRNA binding and mRNA degradation directly from RNA sequence. REPRESS was trained on AGO2-CLIP, miR-eCLIP and Degradome-Seq data profiling millions of microRNA binding and mRNA degradation sites across multiple cell types in human and mouse. It reveals biology that other state-of-the-art methods did not, such as identifying repressive non-canonical miRNA target sites and decoding the regulatory effects of sequence context and miRNA binding site multiplicity. REPRESS outperforms other advanced methods and neural architectures on a comprehensive suite of seven orthogonal tasks, including identifying genetic variants that affect microRNA binding, predicting out-of-distribution data from massively parallel reporter assays, and predicting canonical and non-canonical miRNA mediated repression. To demonstrate the general utility of REPRESS, we show that it provides insights into novel biology and the design of RNA therapeutics. Code is available at : https://github.com/deepgenomics/repress