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During development the human β-globin gene cluster undergoes two switching processes at the embryo-fetal and fetal-adult stages, respectively, involving changes in chromatin remodeling and in transcriptional regulatory networks. In particular, during the perinatal period, the switch from fetal-to-adult globin gene expression leads to fetal globin genes silencing and progressive decline of fetal hemoglobin (HbF). Impaired hemoglobin switching is associated with hereditary persistence of HbF (HPFH), a condition in which the fetal globin genes fail to be completely silenced in adult red blood cells. This condition, when co-inherited with hemoglobinopathies, has great therapeutic potential because elevated HbF levels can ameliorate β-thalassemia and sickle cell anemia. Therefore, there is a growing interest about the complex network of factors that regulate fetal globin genes expression. Here we discuss the activity of transcriptional repressors of fetal globin genes and their potential role as novel therapeutic targets in β-thalassemia.

Hemoglobinopathies are a heterogeneous group of monogenic disorders widespread overall. They are commonly subdivided into three partially overlapping subgroups: structural variants which comprise the sickle cell anemia syndrome; thalassemias, characterized by a reduced rate of synthesis of one or more globin chains of hemoglobin; conditions of high persistence of fetal hemoglobin in adulthood (HPFH) (Weatherall & Clegg, 2001). As a group, they are the commonest monogenic disorders in the world population. It is thought that the high prevalence of these defects could be due to selective advantage of the carrier state to malaria infection. However, in spite of epidemiological evidences supporting this hypothesis as well as of extensive hematological studies, the mechanisms underlying this protection still remain unknown. It is, however, evident that as a consequence of this positive selection, these diseases are mostly common in geographic areas extending from the Mediterranean region through tropical countries including Sub-Saharian Africa, the Middle East, India, Southeast Asia and Indonesia, where malaria was or still is endemic (Weatherall & Clegg, 2001). In many of these areas the estimated frequencies of these disorders range from 3 to 10 percent, even though in some specific areas the carrier frequencies may be higher, reaching 80-90% in some tribal populations in India (Harteveld & Higgs, 2010). Because of their high frequencies, different hemoglobin defects may be co-inherited, giving rise to an extremely complex series of genotypes and clinical phenotypes. In fact, in many regions thalassemic defects coexist with structural Hb variants; it is also quite common for individuals from areas at high frequency of thalassemic defects to inherit genes for more than one type of thalassemia. Furthermore, some Hb variants are synthesized at reduced rate or are highly instable, leading both to functional and structural deficiency of the affected globin chain, thus resulting in a thalassemic condition, generally showing dominant inheritance. These complex interactions contribute to generate a wide range of clinical disorders that, taken together, constitute the thalassemic syndromes (Weatherall, 2001). The complex and heterogeneous spectrum of molecular defects underlying these inherited conditions is regionally specific and in most cases the geographic and ethnic distributions have been determined, providing support for prevention programs based on screening, genetic counselling and prenatal diagnosis in couples at risk.