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A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy.


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.

SUBMITTER: Barde I 

PROVIDER: S-EPMC3678075 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy.

Barde Isabelle I   Rauwel Benjamin B   Marin-Florez Ray Marcel RM   Corsinotti Andrea A   Laurenti Elisa E   Verp Sonia S   Offner Sandra S   Marquis Julien J   Kapopoulou Adamandia A   Vanicek Jiri J   Trono Didier D  

Science (New York, N.Y.) 20130314 6130


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 ex  ...[more]

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