Relative abundance of PU.1, a transcription factor essential during hematopoiesis, controls lineage fate decisions. In Molecular Cell, Staber et al. examine PU.1 activity in mouse hematopoietic stem cells (HSCs). PU.1 regulates its own expression by binding to the promoter and an upstream regulatory element (URE) at −14 kb relative to the transcriptional start site. Mutation of the URE Pu.1 site decreases expression of PU.1 in HSCs but not macrophages. Mice harboring such hypomorphic mutations have HSCs that show reduced long-term repopulation potential and exhibit hematopoietic failure after repeated stressing. PU.1 acts by inhibiting genes that promote cell proliferation and activates those encoding cell-cycle inhibitors. Thus PU.1 is required to maintain HSC quiescence and prevent exhaustion of the HSC pool.

Mol. Cell 49, 934–946 (2013)