FBXO11-mediated protein degradation enables red cell differentiation. In expanding red cell progenitors, differentiation-associated genes are repressed by epigenetic factors such as the polycomb complex. To enter terminal differentiation, the E3 ubiquitin ligase FBXO11 initiates the proteasomal degradation of chromatin factor BAHD1. As a result, repressive factors are no longer recruited to erythroid genes, which allows GATA1 to activate red cell genes required for terminal differentiation.