Role of the Cold Shock Domain Protein A in the transcriptional regulation of gamma-globin gene expression.
Résumé
Impaired switching from fetal haemoglobin (HbF) to adult globin gene expression leads to hereditary persistence of fetal haemoglobin (HPFH) in adult life. This is of prime interest because elevated HbF levels ameliorate beta-thalassaemia and sickle cell anaemia. Fetal haemoglobin levels are regulated by complex mechanisms involving factors linked or not to the beta-globin gene locus. To search for factors putatively involved in gamma-globin gene expression, we examined the reticulocyte transcriptome of three siblings who had different HbF levels and different degrees of beta-thalassaemia severity although they had the same alpha- and beta-globin gene cluster genotypes. By mRNA differential display we isolated the cDNA coding for the cold shock domain protein A (CSDA), also known as dbpA, previously reported to interact in vitro with the gamma-globin gene promoter. Expression studies performed in K562 and in primary erythroid cells showed an inverse relationship between gamma-globin and CSDA expression levels. Functional studies performed by Chromatin Immunoprecipitation and reporter gene assays in K562 cells demonstrated that CSDA is able to bind the promoter of the gamma-globin gene and to suppress its expression. Therefore, our study demonstrates that CSDA is a trans-acting repressor factor of gamma-globin gene expression and contributes to modulate the HPFH phenotype.
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