A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy.
Science, 2013/4/19;340(6130):350-3.
Barde I[1], Rauwel B, Marin-Florez RM, Corsinotti A, Laurenti E, Verp S, Offner S, Marquis J, Kapopoulou A, Vanicek J, Trono D
Affiliations
PMID: 23493425DOI: 10.1126/science.1232398
Impact factor: 63.714
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.
MeSH terms
Anemia; Animals; Autophagy; Erythroblasts; Erythropoiesis; Female; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Mitochondria; Mitochondrial Proteins; Nuclear Proteins; Repressor Proteins; Transcription Factors; Tripartite Motif-Containing Protein 28; Zinc Fingers
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