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 rea
ctivate fetal globin genes. If there is a reciprocal elevation of gamma-glo
bin expression upon repression, this approach could be useful in additional
hemoglobinopathies, We previously showed that repression of the beta-globi
n gene appears to be mediated through two DNA sequences, silencers I and II
, and identified a protein termed BP1 which binds to both silencer sequence
s. In this study, we cloned two cDNAs encoding proteins which bind to an ol
igonucleotide in silencer I containing a BP1 binding site. These cDNAs corr
espond to HMG-I and HMG-Y, isoforms regarded as architectural proteins. We
demonstrate that binding of HMG-I(Y) to this ogligonucleotide causes bendin
g/flexure of the DNA, HMG-I(Y) also binds to a second oligonudeotide contai
ning a BP1 binding site located in a negative control region upstream of th
e 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 exp
ressed in human tissues that do not express beta-globin, being present in 4
8 of 50 tissues and six hematopoietic cell lines examined. Furthermore, HMG
-I(Y) expression is down-regulated during differentiation of primary erythr
oid 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 HM
G-I(Y) helps to determine the repressive state of the beta-globin gene. (C)
1999 Wiley-Liss, Inc.