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Gamma-globin gene expression in chemical inducer of dimerization (cid)-dependent multipotential cells established from human beta-globin locus yeast artificial chromosome (beta-yac) transgenic mice

Academic Article
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Overview

authors

  • Blau, C. A.
  • Barbas III, Carlos
  • Bomhoff, A. L.
  • Neades, R.
  • Yan, J.
  • Navas, P. A.
  • Peterson, K. R.

publication date

  • 2005

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Identification of trans-acting factors or drugs capable of reactivating gamma-globin gene expression is complicated by the lack of suitable cell lines. Human K562 cells co-express epsilon- and gamma-globin but not beta-globin; transgenic mouse erythroleukemia 585 cells express predominantly human beta-globin but also gamma-globin; and transgenic murine GM979 cells co-express human gamma-and beta-globin. Human beta-globin locus yeast artificial chromosome transgenic mice display correct developmental regulation of beta-like globin gene expression. We rationalized that cells established from the adult bone marrow of these mice might express exclusively beta-globin and therefore could be employed to select or screen inducers of gamma-globin expression. A thrombopoietin receptor derivative that brings the proliferative status of primary mouse bone marrow cells under control of a chemical inducer of dimerization was employed to institute and maintain these cell populations. Human beta-globin was expressed, but gamma-globin was not; a similar expression pattern was observed in cells derived from fetal liver. gamma-Globin expression was induced upon exposure to 5-azacytidine, in cells derived from -117 Greek hereditary persistence of fetal hemoglobin human beta-globin locus yeast artificial chromosome (beta-YAC) mice, showing that the hereditary persistence of fetal hemoglobin (HPFH) phenotype was maintained in these cells or was reactivated by an artificial zinc finger-gamma-globin transcription factor and the previously identified fetal globin transactivators fetal Krüppel-like factor (FKLF) and fetal globin-increasing factor (FGIF). These cells may be useful for identifying transcription factors that reactivate gamma-globin synthesis or screening gamma-globin inducers for the treatment of sickle cell disease or beta-thalassemia.

subject areas

  • Animals
  • Azacitidine
  • Bone Marrow Cells
  • Chromosomes, Artificial, Yeast
  • Dimerization
  • Fetal Hemoglobin
  • Gene Expression Regulation, Developmental
  • Globins
  • Humans
  • Liver
  • Mice
  • Mice, Transgenic
  • Multipotent Stem Cells
  • Phenotype
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M504402200

PubMed ID

  • 16131492
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Additional Document Info

start page

  • 36642

end page

  • 36647

volume

  • 280

issue

  • 44

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