Barde, IsabelleRauwel, BenjaminMarin-Flórez, Ray MarcelCorsinotti, AndreaLaurenti, ElisaVerp, SoniaOffner, Sandra EloiseMarquis, JulienKapopoulou, AdamandiaVanicek, JiriTrono, Didier2013-03-252013-03-252013-03-25201310.1126/science.1232398https://infoscience.epfl.ch/handle/20.500.14299/90539WOS:000317657500055During hematopoiesis, lineage- and stage-specific transcription factors work in concert with chromatin modifiers to direct the differentiation of all blood cells. Here, we explored the role of KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor KAP1 in this process. Hematopoietic-restricted deletion of Kap1 in the mouse resulted in severe hypoproliferative anemia. Kap1-deleted erythroblasts failed to induce mitophagy-associated genes and retained mitochondria. This was due to persistent expression of microRNAs targeting mitophagy transcripts, itself secondary to a lack of repression by stage-specific KRAB-ZFPs. The KRAB/KAP1-miRNA regulatory cascade is evolutionary conserved, as it also controls mitophagy during human erythropoiesis. Thus, a multilayered transcription regulatory system is present, where protein- and RNA-based repressors are superimposed in combinatorial fashion to govern the timely triggering of an important differentiation event.text::journal::journal article::research article