A KRAB/KAP1-microRNA cascade regulates erythropoiesis through the stage-specific control of mitophagy

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. Erythropoiesis releases about one hundred billion new red cells every day from the human adult bone marrow. This process is initiated by the differentiation of hematopoietic stem cells (HSC) into the earliest erythroid progenitor identified ex vivo, the slowly growing burst-forming unit-erythroid (BFU-E). This cell morphs into the rapidly dividing CFU-E (colony-forming

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