title: A novel role for nuclear factor-erythroid 2 in erythroid maturation by modulation of mitochondrial autophagy.
abstract: We have recently demonstrated that the transcription factor nuclear factor-erythroid 2, which is critical for erythroid maturation and globin gene expression, plays an important role in the pathophysiology of myeloproliferative neoplasms. Myeloproliferative neoplasm patients display elevated levels of nuclear factor-erythroid 2 and transgenic mice overexpressing the transcription factor develop myeloproliferative neoplasm, albeit, surprisingly without erythrocytosis. Nuclear factor-erythroid 2 transgenic mice show both a reticulocytosis and a concomitant increase in iron deposits in the spleen, suggesting both enhanced erythrocyte production and increased red blood cell destruction. We therefore hypothesized that elevated nuclear factor-erythroid 2 levels may lead to increased erythrocyte destruction by interfering with organelle clearance during erythroid maturation. We have previously shown that nuclear factor-erythroid 2 overexpression delays erythroid maturation of human hematopoietic stem cells. Here we report that increased nuclear factor-erythroid 2 levels also impede murine maturation by retarding mitochondrial depolarization and delaying mitochondrial elimination. In addition, ribosome autophagy is delayed in transgenics. We demonstrate that the autophagy genes NIX and ULK1 are direct novel nuclear factor-erythroid 2 target genes, as these loci are bound by nuclear factor-erythroid 2 in chromatin immunoprecipitation assays. Moreover, Nix and Ulk1 expression is increased in transgenic mice and in granulocytes from polycythemia vera patients. This is the first report implying a role for nuclear factor-erythroid 2 in erythroid maturation by affecting autophagy.
authors.affiliation: Clinic for Internal Medicine I, Division of Molecular Hematology, University of Freiburg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Gothwal
authors.affiliation: Clinic for Internal Medicine I, Division of Molecular Hematology, University of Freiburg, Germany.
authors.forename: Julius
authors.initials: J
authors.lastname: Wehrle
authors.affiliation: Department of Pathology, Medical Center, Faculty of Medicine, University of Freiburg, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Aumann
authors.affiliation: Clinic for Internal Medicine I, Division of Molecular Hematology, University of Freiburg, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Zimmermann
authors.affiliation: Clinic for Internal Medicine I, Division of Molecular Hematology, University of Freiburg, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Gründer
authors.affiliation: Clinic for Internal Medicine I, Division of Molecular Hematology, University of Freiburg, Germany pahl@uni-freiburg.de.
authors.forename: Heike L
authors.initials: HL
authors.lastname: Pahl
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D015415:Biomarkers; D041905:Erythroid Cells / Q000166:cytology* / Q000378:metabolism*; D004920:Erythropoiesis / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D016130:Immunophenotyping; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D050983:NF-E2 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D010659:Phenylhydrazines / Q000494:pharmacology; D011087:Polycythemia Vera / Q000235:genetics / Q000378:metabolism; D012156:Reticulocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism
chemical_list: D015415:Biomarkers; D050983:NF-E2 Transcription Factor; D010659:Phenylhydrazines; C030299:phenylhydrazine