title: Myeloid zinc finger 1 (Mzf1) differentially modulates murine cardiogenesis by interacting with an Nkx2.5 cardiac enhancer.
abstract: Vertebrate heart development is strictly regulated by temporal and spatial expression of growth and transcription factors (TFs). We analyzed nine TFs, selected by in silico analysis of an Nkx2.5 enhancer, for their ability to transactivate the respective enhancer element that drives, specifically, expression of genes in cardiac progenitor cells (CPCs). Mzf1 showed significant activity in reporter assays and bound directly to the Nkx2.5 cardiac enhancer (Nkx2.5 CE) during murine ES cell differentiation. While Mzf1 is established as a hematopoietic TF, its ability to regulate cardiogenesis is completely unknown. Mzf1 expression was significantly enriched in CPCs from in vitro differentiated ES cells and in mouse embryonic hearts. To examine the effect of Mzf1 overexpression on CPC formation, we generated a double transgenic, inducible, tetOMzf1-Nkx2.5 CE eGFP ES line. During in vitro differentiation an early and continuous Mzf1 overexpression inhibited CPC formation and cardiac gene expression. A late Mzf1 overexpression, coincident with a second physiological peak of Mzf1 expression, resulted in enhanced cardiogenesis. These findings implicate a novel, temporal-specific role of Mzf1 in embryonic heart development. Thereby we add another piece of puzzle in understanding the complex mechanisms of vertebrate cardiac development and progenitor cell differentiation. Consequently, this knowledge will be of critical importance to guide efficient cardiac regenerative strategies and to gain further insights into the molecular basis of congenital heart malformations.
authors.affiliation: Department of Experimental Surgery, Department of Cardiovascular Surgery, Deutsches Herzzentrum München, Technische Universität München (TUM), Munich, Germany.
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Doppler
authors.affiliation: Department of Experimental Surgery, Department of Cardiovascular Surgery, Deutsches Herzzentrum München, Technische Universität München (TUM), Munich, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Werner
authors.affiliation: Department of Experimental Surgery, Department of Cardiovascular Surgery, Deutsches Herzzentrum München, Technische Universität München (TUM), Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Barz
authors.affiliation: Department of Experimental Surgery, Department of Cardiovascular Surgery, Deutsches Herzzentrum München, Technische Universität München (TUM), Munich, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Lahm
authors.affiliation: Department of Experimental Surgery, Department of Cardiovascular Surgery, Deutsches Herzzentrum München, Technische Universität München (TUM), Munich, Germany.
authors.forename: Marcus-André
authors.initials: MA
authors.lastname: Deutsch
authors.affiliation: Department of Experimental Surgery, Department of Cardiovascular Surgery, Deutsches Herzzentrum München, Technische Universität München (TUM), Munich, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Dreßen
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München (TUM), Munich, Germany; Clinical Cooperation Groups "Antigen-specific Immunotherapy" and "Immune-Monitoring", Helmholtz Center Munich (Neuherberg), TUM, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schiemann
authors.affiliation: Department of Experimental Surgery, Department of Cardiovascular Surgery, Deutsches Herzzentrum München, Technische Universität München (TUM), Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Voss
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Harvard Medical School, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Serge
authors.initials: S
authors.lastname: Gregoire
authors.affiliation: Division of Cardiovascular Medicine, Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Rajarajan
authors.initials: R
authors.lastname: Kuppusamy
authors.affiliation: Division of Cardiovascular Medicine, Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Wu
authors.affiliation: Department of Experimental Surgery, Department of Cardiovascular Surgery, Deutsches Herzzentrum München, Technische Universität München (TUM), Munich, Germany; DZHK (German Center for Cardiovascular Research) - partner site Munich Heart Alliance, Munich, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Lange
authors.affiliation: Department of Experimental Surgery, Department of Cardiovascular Surgery, Deutsches Herzzentrum München, Technische Universität München (TUM), Munich, Germany; DZHK (German Center for Cardiovascular Research) - partner site Munich Heart Alliance, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Krane
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D003198:Computer Simulation; D053595:Embryonic Stem Cells / Q000166:cytology; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006321:Heart / Q000196:embryology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; C490095:Mzf1 protein, mouse; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors