Structural and functional characterization of CSDA protein complexes involved in the modulation of fetal globin gene expression

Impaired switching from fetal hemoglobin (HbF) to adult globin gene expression leads to hereditary persistence of fetal hemoglobin (HPFH) in adult life. This is of prime interest because elevated HbF levels ameliorate beta-thalassemia and sickle cell anemia. Fetal hemoglobin 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-thalassemia severity although they had the same alpha- and beta-globin gene cluster genotypes. Using a differential mRNA display approach, we identified a cDNA of the cold shock domain protein A (CSDA), a trans-acting factor previously reported to interact in vitro with the gamma-globin gene promoter. Real time quantitative analysis in the three patients and CSDA expression studies in the human erythroleukemic K562 cell line showed an inverse relationship between gamma-globin and CSDA mRNA levels. Our study demonstrates that CSDA acts as a repressor of gamma-globin genes in vivo and is a novel quantitative trait locus for HPFH. We expect our findings pave the way to novel therapeutic strategies, based on gene-silencing, for the treatment of hemoglobinopathies.