Mathematical analysis of G1/S sub-networks in hematopoietic proliferation: Sequential and lineage-specific activation.

Commitment to the cell division cycle constrains other fate choices at the single-cell level. Hence the molecular network controlling the G1/S transition must be coordinated with developmental phases. Healthy hematopoiesis relies on shifts in cell cycle dynamics that balance proliferation and differentiation of hematopoietic stem cells and lineage progenitors, offering an ideal model system to study this coordination. Using computational analysis of published single-cell transcriptomics profiles of human bone marrow and mathematical modeling, we demonstrate that variations in the expression of cyclin D- and cyclin E-centered sub-modules of the G1/S network carve out distinct trajectories from G1 to S, explaining the distinct proliferation properties of hematopoietic cell types evolving in the same microenvironment. We map 68 hematopoietic cell types to specific model parameters, and identify their individual route through G1/S. This theoretical work provides mechanistic insight into hematopoietic proliferation that could guide experimental testing and the design of more nuanced cell cycle-targeting pharmacological strategies.