Summary
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 interrogated 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 identifies potential avenues for manipulating cell identity.
Highlights
There exists a point of irreversible commitment in granulocytic differentiation
Chromatin state dynamics establish the transition from self-renewal to differentiation commitment
Reduced chromatin accessibility underlies an irreversible loss of regulatory site access
Restoration of a transcription factor feedback loop alters the differentiation commitment point
Competing Interest Statement
DBS is a co-founder and holds equity in Clear Creek Bio and SAFI Biosolutions. He is a consultant for Keros Therapeutics. DTS is a co-founder and equity holder in Fate Therapeutics, Clear Creek Bio and LifeVault Bio; he is a director co-founder and equity holder in Magenta Therapeutics, he is a director and equity holder in Agios Pharmaceuticals and Editas Medicine, he is a consultant for FOG Pharma and VCanBio, a DSMB member for Alexion and a sponsored research recipient from Novartis. YS is a co-founder and holds equity in Constellation Pharmaceuticals, Inc, Athelas Therapeutics, Inc and K36 Therapeutics, Inc. YS also holds equity in Imago Biosciences Inc, and is a consultant for Active Motif, Inc.
Footnotes
↵† Lead contact: M. Andrés Blanco