Elevating fetal hemoglobin: recently discovered regulators and mechanisms

Abstract

It has been known for over half a century that throughout ontogeny, humans produce different forms of hemoglobin, a tetramer of α- and β-like hemoglobin chains. The switch from fetal to adult hemoglobin occurs around the time of birth when erythropoiesis shifts from the fetal liver to the bone marrow. Naturally, diseases caused by defective adult β-globin genes, such as sickle cell disease and β-thalassemia, manifest themselves as the production of fetal hemoglobin fades. Reversal of this developmental switch has been a major goal to treat these diseases and has been a driving force to understand its underlying molecular biology. Several review articles have illustrated the long and at times arduous paths that led to the discovery of the first transcriptional regulators involved in this process. Here, we survey recent developments spurred by the discovery of CRISPR tools that enabled for the first time high-throughput genetic screens for new molecules that impact the fetal-to-adult hemoglobin switch. Numerous opportunities for therapeutic intervention have thus come to light, offering hope for effective pharmacologic intervention for patients for whom gene therapy is out of reach.

Graphical abstract

Figure 1.

Select regulators of the fetal-to-adult hemoglobin switch. The β-globin locus on chromosome 11 is shown with the LCR and developmentally arrayed β-like globin genes. Activators are noted above and repressors (direct and indirect) are noted below. Both NF-Y and BAF also activate adult globins. Developmentally controlled factors with differential expression between fetal and adult tissues are indicated. Regulators with the most advanced targeted therapies are highlighted in yellow. Dotted lines indicate direct posttranscriptional regulation and dashed lines indicate indirect control.