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

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

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 309 KB
• Volume: 60
• Category: Article
• ISSN: 0361-8609
• DOI: 10.1002/(sici)1096-8652(199901)60:1<27::aid-ajh6>3.0.co;2-0

✦ Synopsis

Proteins involved in repression of the human ␤-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 ␥-globin expression upon repression, this approach could be useful in additional hemoglobinopathies. We previously showed that repression of the ␤-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 ogligonucleotide 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 ␦-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 ␤-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 ␤-globin gene.