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Science ; 340(6130): 350-3, 2013 Apr 19.
Article in English | MEDLINE | ID: mdl-23493425

ABSTRACT

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.


Subject(s)
Autophagy/genetics , Erythroblasts/metabolism , Erythropoiesis/genetics , MicroRNAs/metabolism , Mitochondria/physiology , Nuclear Proteins/metabolism , Repressor Proteins/metabolism , Transcription Factors/metabolism , Zinc Fingers , Anemia/genetics , Animals , Erythroblasts/ultrastructure , Female , Male , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , MicroRNAs/genetics , Mitochondria/genetics , Mitochondrial Proteins/metabolism , Nuclear Proteins/genetics , Repressor Proteins/genetics , Tripartite Motif-Containing Protein 28
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