Binding of HMG-I(Y) elicits structural changes in a silencer of the human β-globin gene

Michael B. Chase, Susanne B. Haga, W. David Hankins, Donna M. Williams, Zhigang Bi, Jeffrey W. Strovel, Christine Obriecht, Patricia E. Berg

Research output: Contribution to journalArticlepeer-review

Abstract

Proteins involved in repression of the human β-globin gene may be useful in the treatment of sickle cell anemia, in conjunction with therapy to reactivate fetal globin genes. If there is a reciprocal elevation of γ- globin expression upon repression, this approach could be useful in additional hemoglobinopathies. We previously showed that repression of the β-globin gene appears to be mediated through two DNA sequences, silencers I and II, and identified a protein termed BP1 which binds to both silencer sequences. In this study, we cloned two cDNAs encoding proteins which bind to an oligonucleotide in silencer I containing a BP1 binding site. These cDNAs correspond to HMG-I and HMG-Y, isoforms regarded as architectural proteins. We demonstrate that binding of HMG-I(Y) to this oligonucleotide causes bending/flexure of the DNA. HMG-I(Y) also binds to a second oligonucleotide containing a BP1 binding site located in a negative control region upstream of the δ-globin gene, suggesting a role for HMG-I(Y) in repression of adult globin genes. Expression studies revealed that HMG-I(Y) is ubiquitously expressed in human tissues that do not express β-globin, being present in 48 of 50 tissues and six hematopoietic cell lines examined. Furthermore, HMG- I(Y) expression is down-regulated during differentiation of primary erythroid cells. We present a model in which HMG-I(Y) alters DNA conformation to allow binding of repressor proteins, and in which the relative amount of HMG-I(Y) helps to determine the repressive state of the β-globin gene.

Original languageEnglish (US)
Pages (from-to)27-35
Number of pages9
JournalAmerican Journal of Hematology
Volume60
Issue number1
DOIs
StatePublished - 1999
Externally publishedYes

Keywords

  • Beta globin
  • HMG-I(Y)
  • Repressors

ASJC Scopus subject areas

  • Hematology

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