Editors' ChoiceErythropoiesis

Repressing the Repressors of Mitophagy

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Science Signaling  23 Apr 2013:
Vol. 6, Issue 272, pp. ec92
DOI: 10.1126/scisignal.2004260

A critical, final step in the differentiation of erythrocytes is the loss of intracellular organelles. Barde et al. found that knocking out the gene that encodes the transcriptional corepressor KAP1 [also known as tripartite motif protein 28 (TRIM28)] in mice resulted in accumulation of immature erythrocytes (erythroblasts) at the expense of mature erythrocytes. Compared with erythroblasts from wild-type mice, the mutant erythroblasts contained more mitochondria and showed decreased abundance of transcripts encoding proteins that mediate mitophagy. By transcriptional profiling, microRNAs miR-351, miR-503, and miR-322 showed increased expression in Kap1-knockout erythroblasts. The abundance of miR-351, which targeted a transcript required for mitophagy, decreased as wild-type erythroblasts matured, and overexpressing miR-351 blocked differentiation and caused accumulation of mitochondria in cultured mouse erythroleukemia cells. These three miRNAs are located near one another on the X chromosome, and KAP1 was associated with DNA near this miRNA gene cluster. KAP1 does not bind to DNA on its own but cooperates with KRAB-containing zinc finger proteins (KRAB-ZFPs). The authors identified several KRAB-ZFPs that were present only in erythroblasts and not other hematopoietic cells. Zfp689 and Zfp13 were expressed in late-stage erythroblasts and repressed expression of a reporter driven by the KAP1 binding site from the miRNA cluster in cultured erythroleukemia cells. When transplanted into irradiated mice, hematopoietic stem cells expressing short hairpin RNAs (shRNAs) targeting Zfp689, Zfp13, or Kap1 generated few mature erythrocytes and gave rise to erythroblasts that showed increased miR-351 abundance. Experiments in cultured human erythroleukemia cells and cord blood cells were consistent with the findings in mice. Thus, KRAB-ZFPs and KAP1 trigger the elimination of mitochondria during late stages of erythrocyte differentiation by cooperating to repress the transcription of miRNAs that target transcripts encoding mitophagy factors.

I. Barde, B. Rauwel, R. M. Marin-Florez, A. Corsinotti, E. Laurenti, S. Verp, S. Offner, J. Marquis, A. Kapopoulou, J. Vanicek, D. Trono, A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy. Science 340, 350–353 (2013). [Abstract] [Full Text]

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