Single-cell multiomics reveals the oscillatory dynamics of mRNA metabolism and chromatin accessibility during the cell cycle

Abstract The cell cycle is a tightly regulated process that requires precise temporal expression of hundreds of cell cycledependent genes. However, the genome-wide dynamics of mRNA metabolism throughout the cell cycle remain uncharacterized. Here, we combined single-cell multiome sequencing, biophysical modeling, and deep learning to quantify rates of mRNA transcription, splicing, nuclear export, and degradation. Our approach revealed that both transcriptional and post-transcriptional processes exhibit distinct oscillatory waves at specific cell cycle phases, with post-transcriptional regulation playing a prominent role in shaping mRNA accumulation. We also observed dynamic changes in chromatin accessibility and transcription factor binding footprints, identifying key regulators underlying the oscillatory dynamics of mRNA. Taken together, our approach uncovered a high-resolution map of RNA metabolism dynamics and chromatin accessibility, offering new insights into the temporal control of gene expression in proliferating cells. Highlights FourierCycle combines single-cell multiome sequencing, deep learning, and biophysical modeling to quantify gene-specific rates of mRNA metabolism during the cell cycle Rates of mRNA transcription, nuclear export, and degradation show gene-specific oscillatory waves at distinct cell cycle phases. Post-transcriptional regulation, including mRNA degradation and nuclear export, plays a prominent role in shaping mRNA accumulation during the cell cycle Dynamics of chromatin accessibility and transcription factor binding footprints uncover key regulators underlying the transcriptional control of gene expression Graphical abstract