Assuntos
Proteínas de Transporte/fisiologia , Eritropoese/fisiologia , MicroRNAs/fisiologia , Mitofagia/genética , Proteínas Nucleares/fisiologia , Proteínas Repressoras/fisiologia , Animais , Diferenciação Celular/genética , Humanos , Camundongos , Camundongos Knockout , Transdução de Sinais/fisiologia , Proteína 28 com Motivo TripartidoRESUMO
During hematopoiesis, lineage- and stage-specific transcription factors work in concert with chromatin modifiers to direct the differentiation of all blood cells. We explored the role of KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor KAP1 in this process. In mice, hematopoietic-restricted deletion of Kap1 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 (miRNAs) targeting mitophagy transcripts, itself secondary to a lack of repression by stage-specific KRAB-ZFPs. The KRAB/KAP1-miRNA regulatory cascade is evolutionarily conserved, as it also controls mitophagy during human erythropoiesis. Thus, a multilayered transcription regulatory system is present, in which protein- and RNA-based repressors are superimposed in combinatorial fashion to govern the timely triggering of an important differentiation event.
