Fig. 1.

Uhrf1 regulates the modes of HSC division, leading to self-renewal or differentiation. Expression of the endogenous Notch inhibitor Numb was used to trace the cell fate of Uhrf1^+/+ or Uhrf1^−/− HSPCs in single-cell division studies. Low Numb expression is associated with maintenance of self-renewal, whereas high Numb expression suggests an acquisition in differentiation potential. SD cell division events, which display higher Numb expression in mother/daughter cell pairs, increases significantly in dividing Uhrf1^−/− HSCs, whereas SS divisions with low Numb expression in mother/daughter cell pairs decreases. The frequency of AD in HSCs does not significantly change in the absence of Uhrf1. The promoter of Gata1, a master regulator of erythroid lineage commitment, is methylated in Uhrf1^+/+ fetal and adult HSCs (black lollipops); however, these modifications are lost in Uhrf1^−/− HSCs (gray lollipops), causing derepression of Gata1 expression and the activation of an erythroid-specific gene expression program. Hypomethylation of the Gata1 promoter was also shown to be enriched in daughter cells displaying high Numb expression, a hallmark of HSCs undergoing differentiation. Loss of DNA methylation maintenance in Uhrf1^−/− HSCs upon methylation causes a rapid depletion of the HSC pool, with a bias toward SD into erythroid lineage cells.