title: Role of the duplicated CCAAT box region in gamma-globin gene regulation and hereditary persistence of fetal haemoglobin.
abstract: Hereditary persistence of fetal haemoglobin (HPFH) is a clinically important condition in which a change in the developmental specificity of the gamma-globin genes results in varying levels of expression of fetal haemoglobin in the adult. The condition is benign and can significantly alleviate the symptoms of thalassaemia or sickle cell anaemia when co-inherited with these disorders. We have examined structure-function relationships in the -117 HPFH gamma promoter by analysing the effect of mutating specific promoter elements on the functioning of the wild-type and HPFH promoters. We find that CCAAT box mutants dramatically affect expression from the HPFH promoter in adult blood but have little effect on embryonic/fetal expression from the wild-type promoter. Our results suggest that there are substantial differences in the structure of the wild-type gamma promoter expressed early in development and the adult HPFH promoter. Together with previous results, this suggests 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 significant implications for attempts to reactivate the gamma promoters in human adults by pharmacological means.
authors.affiliation: Universita Degli Studi di Milano, Dipartimento di Genetica e di Biologia di Microrganisimi, 20133 Milano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Ronchi
authors.forename: M
authors.initials: M
authors.lastname: Berry
authors.forename: S
authors.initials: S
authors.lastname: Raguz
authors.forename: A
authors.initials: A
authors.lastname: Imam
authors.forename: N
authors.initials: N
authors.lastname: Yannoutsos
authors.forename: S
authors.initials: S
authors.lastname: Ottolenghi
authors.forename: F
authors.initials: F
authors.lastname: Grosveld
authors.forename: N
authors.initials: N
authors.lastname: Dillon
mesh_terms: D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D050981:Erythroid-Specific DNA-Binding Factors; D005319:Fetal Hemoglobin / Q000235:genetics*; D005786:Gene Expression Regulation; D005914:Globins / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000196:embryology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism; D015017:Yolk Sac / Q000378:metabolism; D051837:COUP Transcription Factor II
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D005319:Fetal Hemoglobin; D005914:Globins; D009687:Nuclear Proteins; D014157:Transcription Factors; C095569:NR2F2 protein, human; D051837:COUP Transcription Factor II