Metabolic adaptation pilots the differentiation of human hematopoietic cells (scATAC-Seq)

In order to get insight in the role of metabolic perturbations during the first steps of cell differentiation, the phenotype, gene expression profile and chromatin accessibility of CD34+ cells were examined using bulk- and single-cell techniques during the initial 96 hours of in vitro differentiation. Specific enzyme inhibitors targeting key steps of the energy metabolism were employed to induce perturbations and assess their effect. The results support a model whereby energy requirements play the role of initiator of differentiation. According to it, metabolic perturbations induce rapid and non-specific, enabling a state of multi-primed gene expression. A selective re-compaction of the chromatin constrained by the availability of key metabolites essential for repressive epigenetic modifications and by the action of transcription regulator proteins consolidates the phenotypic response of the cells. Human hematopoietic CD34+ cells were grown in Xvivo medium supplemented with cytokines with or without energy metabolism inhibitor (DON, 2-DG or AOA) during 24h. All samples are derived from an initial pool of six healthy donors.