title: E2A Antagonizes PU.1 Activity through Inhibition of DNA Binding.
abstract: Antagonistic interactions between transcription factors contribute to cell fate decisions made by multipotent hematopoietic progenitor cells. Concentration of the transcription factor PU.1 affects myeloid/lymphoid development with high levels of PU.1 directing myeloid cell fate acquisition at the expense of B cell differentiation. High levels of PU.1 may be required for myelopoiesis in order to overcome inhibition of its activity by transcription factors that promote B cell development. The B cell transcription factors, E2A and EBF, are necessary for commitment of multipotential progenitors and lymphoid primed multipotential progenitors to lymphocytes. In this report we hypothesized that factors required for early B cell commitment would bind to PU.1 and antagonize its ability to induce myeloid differentiation. We investigated whether E2A and/or EBF associate with PU.1. We observed that the E2A component, E47, but not EBF, directly binds to PU.1. Additionally E47 represses PU.1-dependent transactivation of the MCSFR promoter through antagonizing PU.1's ability to bind to DNA. Exogenous E47 expression in hematopoietic cells inhibits myeloid differentiation. Our data suggest that E2A antagonism of PU.1 activity contributes to its ability to commit multipotential hematopoietic progenitors to the lymphoid lineages.
authors.affiliation: Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Rogers
authors.affiliation: Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Kristin S
authors.initials: KS
authors.lastname: Owens
authors.affiliation: Biological Science, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kurkewich
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, IN 46617, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Klopfenstein
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Sangeeta R
authors.initials: SR
authors.lastname: Iyer
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.affiliation: Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, USA; Biological Science, University of Notre Dame, Notre Dame, IN 46556, USA; Department of Microbiology and Immunology, Indiana University School of Medicine, South Bend, IN 46617, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Dahl
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics; D022423:Myeloid Cells / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D058127:Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D016173:Macrophage Colony-Stimulating Factor; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D058127:Transcription Factor 3; D000099232:Proto-Oncogene Protein Spi-1; C081976:EBF1 protein, human; C407909:TCF3 protein, human