Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 340 (6130): 350-353

Copyright © 2013 by the American Association for the Advancement of Science

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

Isabelle Barde,1 Benjamin Rauwel,1 Ray Marcel Marin-Florez,2,* Andrea Corsinotti,1,{dagger} Elisa Laurenti,1,{ddagger} Sonia Verp,1 Sandra Offner,1 Julien Marquis,1,§ Adamandia Kapopoulou,1 Jiri Vanicek,2 Didier Trono1,||

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.

1 School of Life Sciences and Frontiers in Genetics Program, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
2 School of Basic Sciences, EPFL, 1015 Lausanne, Switzerland.

* Present address: Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.

{dagger} Present address: Centre for Genomic Regulation, 08003 Barcelona, Spain.

{ddagger} Present address: Campbell Family Institute for Cancer Research, Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

§ Present address: Functional Genomics Core, Nestlé Institute of Health Sciences, EPFL Campus, 1015 Lausanne, Switzerland.

||Corresponding author. E-mail: didier.trono{at}epfl.ch


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
MicroRNA-137 Is a Novel Hypoxia-responsive MicroRNA That Inhibits Mitophagy via Regulation of Two Mitophagy Receptors FUNDC1 and NIX.
W. Li, X. Zhang, H. Zhuang, H.-g. Chen, Y. Chen, W. Tian, W. Wu, Y. Li, S. Wang, L. Zhang, et al. (2014)
J. Biol. Chem. 289, 10691-10701
   Abstract »    Full Text »    PDF »
Deep Vertebrate Roots for Mammalian Zinc Finger Transcription Factor Subfamilies.
H. Liu, L.-H. Chang, Y. Sun, X. Lu, and L. Stubbs (2014)
Genome Biol Evol 6, 510-525
   Abstract »    Full Text »    PDF »
The TRIMming on an erythroid repressor complex.
M. H. Baron (2013)
Blood 122, 3701-3702
   Full Text »    PDF »
TRIM28 is essential for erythroblast differentiation in the mouse.
T. Hosoya, M. Clifford, R. Losson, O. Tanabe, and J. D. Engel (2013)
Blood 122, 3798-3807
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882