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A KRAB/KAP1-miRNA Cascade Regulates Erythropoiesis Through Stage-Specific Control of Mitophagy

Science  19 Apr 2013:
Vol. 340, Issue 6130, pp. 350-353
DOI: 10.1126/science.1232398

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Red in Cell and Marrow

About one hundred billion new red cells are released every day from the adult human bone marrow—the result of a complex differentiation pathway. Barde et al. (p. 350, published online 14 March) show that an essential step in this process, the elimination of mitochondria from maturing erythroblasts through mitophagy, is controlled through the timely induction of specific members of the large family of KRAB-containing zinc finger proteins (KRAB-ZFPs), which, together with their cofactor KAP1, repress the expression of micro-RNAs targeting the transcripts of mitophagy effector genes. This multilayered and combinatorial regulation system provides a level of modularity that may be shared by other physiological processes.

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.

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