Abstract
Hematopoiesis is orchestrated by a succession of lineage- and stage-specific transcription factors working in concert with chromatin modifiers. Here, we explored the role of KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor KAP1 in this process. The hematopoietic-restricted deletion of Kap1 in the mouse resulted in severe hypoproliferative anemia, with Kap1-deleted erythroblasts failing to induce mitophagy-associated genes, hence to eliminate mitochondria. This was due to persistent expression of microRNAs targeting mitophagy transcripts, itself secondary to a lack of repression by stage-specific KRAB-ZFPs. This KRAB/KAP1-microRNA regulatory cascade is evolutionary conserved, as it also controls mitophagy during human erythropoiesis. A multilayered transcription regulatory system is thus unveiled, where protein- and RNA-based repressors are super-imposed in combinatorial fashion to govern the timely triggering of an essential differentiation event.