REGULATION OF HUMAN GLOBIN GENE EXPRESSION

Summary

Principal Investigator: Arthur Bank
Affiliation: Columbia University
Country: USA
Abstract: The long-term goals of this grant are to identify and characterize DNA sequences and trans-acting factors that regulate the expression of the human beta globin gene complex, especially those involved in the switch from gamma to beta synthesis in late fetal life. Several different specific DNA sequences and trans- acting factors have been identified that act at the beta globin gene complex, both at the locus-control region (LCR) and close to individual globin genes which are required for either their optimal erythroid-specific or developmental stage-specific regulation, or both. However, to date, no single factor has been implicated in the switch from human gamma to beta synthesis. We have described a trans-acting protein complex (PYR complex) present primarily in adult hematopoietic cells which binds to pyrimidine-rich sequences, including one located 1 kb upstream of the human delta globin gene (delta PYR binding site) which may function in hemoglobin switching. Recently, we have discovered that PYR complex is a specialized human SWI/SNF-like complex. SWI/SNF complexes are known to disrupt chromatin structure and permit transcription factor binding and gene activation. PYR complex is the first SWI/SNF complex with a DNA sequence- dependent binding site. We have also demonstrated a functional role for the delta PYR binding site in enhancing human gamma to beta switching. In these studies in transgenic mice, we have shown that deletion of this sequence leads to delayed switching. The specific aims of this grant are to: (1) characterize the protein subunits of PYR complex by purification and sequencing; (2) define the structure and configuration of the PYR complex binding site more precisely; (3) determine the general function effects of the complex on chromatin structure; (4) localize the minimal DNA sequence required for the functional effects of the complex on globin switching; (5) search for gene targets of PYR complex action other than those at the human beta globin gene locus in erythroid cells, and in other adult hematopoietic cells that express the complex; and (6) define other SWI/SNF complexes, particularly a putative one at the human alpha globin locus. These studies should provide new insights into the mechanisms controlling the hemoglobin switching. They may result in new approaches to the treatment of the beta thalassemias and sickle cell disease since these diseases are due to abnormal beta globin synthesis and could theoretically be cured by allowing optimal gamma globin synthesis to persist into adult life.
Funding Period: 2000-03-01 - 2004-11-30
more information: NIH RePORT

Top Publications

  1. ncbi Regulation of human fetal hemoglobin: new players, new complexities
    Arthur Bank
    Department of Medicine, Columbia University, New York, NY, USA
    Blood 107:435-43. 2006
  2. ncbi Role of intergenic human gamma-delta-globin sequences in human hemoglobin switching and reactivation of fetal hemoglobin in adult erythroid cells
    Arthur Bank
    Department of Medicine, Columbia University, 701 West 168th St, Rm 1604, New York, NY 10032, USA
    Ann N Y Acad Sci 1054:48-54. 2005
  3. ncbi Ikaros increases normal apoptosis in adult erythroid cells
    Dianne Pulte
    Department of Medicine, Columbia University, New York, NY, USA
    Am J Hematol 81:12-8. 2006
  4. ncbi Activating Notch1 mutations are an early event in T-cell malignancy of Ikaros point mutant Plastic/+ mice
    Simon Mantha
    Department of Medicine, Columbia University, New York, NY 10032, USA
    Leuk Res 31:321-7. 2007

Scientific Experts

  • Arthur Bank
  • Simon Mantha
  • Maureen Ward
  • Dianne Pulte
  • Adolfo Ferrando
  • Jonathan McCafferty
  • Alan Herron
  • Teresa Palomero
  • Christine Richardson
  • Shane T Baker
  • Ellen Ritchie
  • Christine A Richardson
  • Rocio A Lopez

Detail Information

Publications4

  1. ncbi Regulation of human fetal hemoglobin: new players, new complexities
    Arthur Bank
    Department of Medicine, Columbia University, New York, NY, USA
    Blood 107:435-43. 2006
    ....
  2. ncbi Role of intergenic human gamma-delta-globin sequences in human hemoglobin switching and reactivation of fetal hemoglobin in adult erythroid cells
    Arthur Bank
    Department of Medicine, Columbia University, 701 West 168th St, Rm 1604, New York, NY 10032, USA
    Ann N Y Acad Sci 1054:48-54. 2005
    ....
  3. ncbi Ikaros increases normal apoptosis in adult erythroid cells
    Dianne Pulte
    Department of Medicine, Columbia University, New York, NY, USA
    Am J Hematol 81:12-8. 2006
    ..We conclude that normal Ikaros function increases normal apoptosis in erythroid cells. The data also suggest that Ikaros plays a role in apoptosis-mediated events in other normal hematopoietic cell lineages...
  4. ncbi Activating Notch1 mutations are an early event in T-cell malignancy of Ikaros point mutant Plastic/+ mice
    Simon Mantha
    Department of Medicine, Columbia University, New York, NY 10032, USA
    Leuk Res 31:321-7. 2007
    ..Mice acquired Notch1 mutations in lymph nodes as early as 7 weeks. Thus, combined Notch1 and Ikaros dysfunction can be a significant early event in T-cell proliferation and tumorigenesis...