The Onset of Myeloid Differentiation in Hematopoietic Progenitors In Vivo is Coordinated with S-phase Progression

Hematopoiesis produces diverse cell types in large quantities. How hematopoietic stem cells (HSCs) initiate lineage differentiation in vivo is not known. Here, we jointly measure chromatin accessibility and transcriptomes in single stem and progenitor cells and uncover a tight interplay between cell-cycle progression and the onset of differentiation. The cell cycle continuously accelerates as HSCs transition to uncommitted multipotent progenitors. In these uncommitted progenitors, proliferative activation is followed by the opening of myeloid-specific chromatin loci in S phase and, subsequently, myeloid gene expression. S phase-coupled onset of myeloid differentiation becomes quantitatively enhanced in emergency myelopoiesis. At the molecular level, we find that chromatin occupancy by HOXA9 – a key transcription factor of uncommitted progenitors – predicts whether the transition through S phase will initiate myelopoiesis, or whether the uncommitted progenitor state will be retained. Taken together, our findings provide a mechanistic framework for the onset of myeloid lineage differentiation in vivo .