Chromatin-state barriers enforce an irreversible mammalian cell fate decision

Stem and progenitor cells have the capacity to balance self-renewal and differentiation. Hematopoietic myeloid progenitors replenish more than 25 billion terminally differentiated neutrophils every day under homeostatic conditions and can increase this output in response to stress or infection. At what point along the spectrum of maturation do progenitors lose capacity for self-renewal and become irreversibly committed to differentiation? Using a system of conditional myeloid development that can be toggled between self-renewal and differentiation, we interrogate determinants of this “point of no return” in differentiation commitment. Irreversible commitment is due primarily to loss of open regulatory site access and disruption of a positive feedback transcription factor activation loop. Restoration of the transcription factor feedback loop extends the window of cell plasticity and alters the point of no return. These findings demonstrate how the chromatin state enforces and perpetuates cell fate and identify potential avenues for manipulating cell identity. [Display omitted] •There exists a point of irreversible commitment in granulocytic differentiation•Chromatin-state dynamics establish the transition from self-renewal to differentiation•Reduced chromatin accessibility underlies irreversible loss of regulatory site access•Restoration of a transcription factor feedback loop alters differentiation commitment Blanco et al. investigate the balance between self-renewal and differentiation and the mechanism of irreversible cell fate commitment. Using a model of conditional myeloid development, they find that loss of accessible chromatin and disruption of a transcription factor feedback loop underlies the “point of no return” in terminal myeloid differentiation.