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

The cell cycle is a tightly regulated process that requires precise temporal expression of hundreds of cell cycle-dependent 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. Overall design: Multiome profiling, snRNA-seq + snATAC-seq, of mouse embryonic stem cells culture in 2i and LIF in serum supplemented conditions