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

Published

Journal Article

Proteins involved in repression of the human beta-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 gamma-globin expression upon repression, this approach could be useful in additional hemoglobinopathies. We previously showed that repression of the beta-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 delta-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 beta-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 beta-globin gene.

Full Text

Duke Authors

Cited Authors

  • Chase, MB; Haga, SB; Hankins, WD; Williams, DM; Bi, Z; Strovel, JW; Obriecht, C; Berg, PE

Published Date

  • January 1999

Published In

Volume / Issue

  • 60 / 1

Start / End Page

  • 27 - 35

PubMed ID

  • 9883803

Pubmed Central ID

  • 9883803

International Standard Serial Number (ISSN)

  • 0361-8609

Digital Object Identifier (DOI)

  • 10.1002/(sici)1096-8652(199901)60:1<27::aid-ajh6>3.0.co;2-0

Language

  • eng

Conference Location

  • United States