LAUSR

Significance The circadian clock is an internal molecular 24-h timer that is critical to life on Earth. We describe a series of artificial intelligence (AI)– and machine learning (ML)–based approaches that enable more cost-effective analysis and insight into circadian regulation and function. Throughout the manuscript, we illuminate what is inside the ML “black box” via explanation or interpretation of predictive ML models. Using this interpretation of our models, we derive biological insights into why a prediction was made, alongside accurate predictions. Most innovatively, we use only DNA sequence features for accurate circadian gene expression prediction. Using explainable AI, we define possible, responsible regulatory elements as we make these predictions; this critically requires no prior knowledge of regulatory elements. The circadian clock is an important adaptation to life on Earth. Here, we use machine learning to predict complex, temporal, and circadian gene expression patterns in Arabidopsis. Most significantly, we classify circadian genes using DNA sequence features generated de novo from public, genomic resources, facilitating downstream application of our methods with no experimental work or prior knowledge needed. We use local model explanation that is transcript specific to rank DNA sequence features, providing a detailed profile of the potential circadian regulatory mechanisms for each transcript. Furthermore, we can discriminate the temporal phase of transcript expression using the local, explanation-derived, and ranked DNA sequence features, revealing hidden subclasses within the circadian class. Model interpretation/explanation provides the backbone of our methodological advances, giving insight into biological processes and experimental design. Next, we use model interpretation to optimize sampling strategies when we predict circadian transcripts using reduced numbers of transcriptomic timepoints. Finally, we predict the circadian time from a single, transcriptomic timepoint, deriving marker transcripts that are most impactful for accurate prediction; this could facilitate the identification of altered clock function from existing datasets.