ROLE OF THE DUPLICATED CCAAT BOX REGION IN GAMMA-GLOBIN GENE-REGULATION AND HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN

Hereditary persistence of fetal haemoglobin (HPFH) is a clinically imp ortant condition in which a change in the developmental specificity of the gamma-globin genes results in varying levels of expression of fet al haemoglobin in the adult, The condition is benign and can significa ntly alleviate the symptoms of thalassaemia or sickle cell anaemia whe n co-inherited with these disorders, We have examined structure-functi on relationships in the -117 HPFH gamma promoter by analysing the effe ct of mutating specific promoter elements on the functioning of the wi ld-type and HPFH promoters, We find that CCAAT box mutants dramaticall y affect expression from the HPFH promoter in adult blood but have lit tle effect on embryonic/fetal expression from the wild-type promoter. Our results suggest that there are substantial differences in the stru cture of the wild-type gamma promoter expressed early in development a nd the adult HPFH promoter. Together with previous results, this sugge sts that gamma silencing is a complex multifactorial phenomenon rather than being the result of a simple repressor binding to the promoter, We present a model for gamma-globin gene silencing that has significan t implications for attempts to reactivate the gamma promoters in human adults by pharmacological means.