Unveil cis-acting combinatorial mRNA motifs by interpreting deep neural network.

Abstract

Cis-acting mRNA elements play a key role in the regulation of mRNA stability and translation efficiency. Revealing the interactions of these elements and their impact plays a crucial role in understanding the regulation of the mRNA translation process, which supports the development of mRNA-based medicine or vaccines. Deep neural networks (DNN) can learn complex cis-regulatory codes from RNA sequences. However, extracting these cis-regulatory codes efficiently from DNN remains a significant challenge. Here, we propose a method based on our toolkit NeuronMotif and motif mutagenesis, which not only enables the discovery of diverse and high-quality motifs but also efficiently reveals motif interactions. By interpreting deep-learning models, we have discovered several crucial motifs that impact mRNA translation efficiency and stability, as well as some unknown motifs or motif syntax, offering novel insights for biologists. Furthermore, we note that it is challenging to enrich motif syntax in datasets composed of randomly generated sequences, and they may not contain sufficient biological signals. The source code and data used to produce the results and analyses presented in this manuscript are available from GitHub (https://github.com/WangLabTHU/combmotif).