title: 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.
authors.affiliation: School of Life Sciences and Frontiers in Genetics Program, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Barde
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rauwel
authors.forename: Ray Marcel
authors.initials: RM
authors.lastname: Marin-Florez
authors.forename: Andrea
authors.initials: A
authors.lastname: Corsinotti
authors.forename: Elisa
authors.initials: E
authors.lastname: Laurenti
authors.forename: Sonia
authors.initials: S
authors.lastname: Verp
authors.forename: Sandra
authors.initials: S
authors.lastname: Offner
authors.forename: Julien
authors.initials: J
authors.lastname: Marquis
authors.forename: Adamandia
authors.initials: A
authors.lastname: Kapopoulou
authors.forename: Jiri
authors.initials: J
authors.lastname: Vanicek
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
mesh_terms: D000740:Anemia / Q000235:genetics; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D004900:Erythroblasts / Q000378:metabolism* / Q000648:ultrastructure; D004920:Erythropoiesis / Q000235:genetics*; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000076183:Tripartite Motif-Containing Protein 28; D016335:Zinc Fingers
chemical_list: C580764:MIRN351 microRNA, 351; D008565:Membrane Proteins; D035683:MicroRNAs; D024101:Mitochondrial Proteins; C501741:Nix protein, mouse; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28