Gene regulatory network inference with popInfer reveals dynamic regulation of hematopoietic stem cell quiescence upon diet restriction and aging.

Inference of gene regulatory networks (GRNs) can reveal cell state transitions from single-cell genomics data. However, obstacles to temporal inference from snapshot data are difficult to overcome. Single-nuclei multiomics data offer means to bridge this gap and derive temporal information from snapshot data using joint measurements of gene expression and chromatin accessibility in the same single cells. We developed popInfer to infer networks that characterize lineage-specific dynamic cell state transitions from joint gene expression and chromatin accessibility data. Benchmarking against alternative methods for GRN inference, we showed that popInfer achieves higher accuracy in the GRNs inferred. popInfer was applied to study single-cell multiomics data characterizing hematopoietic stem cells (HSCs) and the transition from HSC to a multipotent progenitor cell state during murine hematopoiesis across age and dietary conditions. From networks predicted by popInfer, we discovered gene interactions controlling entry to/exit from HSC quiescence that are perturbed in response to diet or aging.