Deep learning of the splicing (epi)genetic code reveals a novel candidate mechanism linking histone modifications to ESC fate decision.

Alternative splicing (AS) is a genetically and epigenetically regulated pre-mRNA processing to increase transcriptome and proteome diversity. Comprehensively decoding these regulatory mechanisms holds promise in getting deeper insights into a variety of biological contexts involving in AS, such as development and diseases. We assembled splicing (epi)genetic code, DeepCode, for human embryonic stem cell (hESC) differentiation by integrating heterogeneous features of genomic sequences, 16 histone modifications with a multi-label deep neural network. With the advantages of epigenetic features, DeepCode significantly improves the performance in predicting the splicing patterns and their changes during hESC differentiation. Meanwhile, DeepCode reveals the superiority of epigenomic features and their dominant roles in decoding AS patterns, highlighting the necessity of including the epigenetic properties when assembling a more comprehensive splicing code. Moreover, DeepCode allows the robust predictions across cell lineages and datasets. Especially, we identified a putative H3K36me3-regulated AS event leading to a nonsense-mediated mRNA decay of BARD1. Reduced BARD1 expression results in the attenuation of ATM/ATR signalling activities and further the hESC differentiation. These results suggest a novel candidate mechanism linking histone modifications to hESC fate decision. In addition, when trained in different contexts, DeepCode can be expanded to a variety of biological and biomedical fields.