Advances in the understanding of haemoglobin switching

Abstract

The study of haemoglobin switching has represented a focus in haematology due in large part to the clinical relevance of the fetal to adult haemoglobin switch for developing targeted approaches to ameliorate the severity of the beta-haemoglobinopathies. Additionally, the process by which this switch occurs represents an important paradigm for developmental gene regulation. In this review, we provide an overview of both the embryonic primitive to definitive switch in haemoglobin expression, as well as the fetal to adult switch that is unique to humans and old world monkeys. We discuss the nature of these switches and models of their regulation. The factors that have been suggested to regulate this process are then discussed. With the increased understanding and discovery of molecular regulators of haemoglobin switching, such as BCL11A, new avenues of research may lead ultimately to novel therapeutic, mechanism-based approaches to fetal haemoglobin reactivation in patients.

Figure 1

A diagram illustrating the developmental switching of the β-like globin gene expression in human (left) and mouse (right). Organization of human and murine β-globin loci, consisting of the linked β-like globin genes (colored boxes), upstream DNaseI hypersensitive sites (HS, red boxes) within the locus control regions (LCR), and downstream 3′HS1, is displayed. Above the graph for the human locus the shifting sites of haematopoiesis are indicated. In the graph for the mouse locus, the content of both endogenous mouse (black straight lines) and exogenous human β-like globins (blue dashed lines) in transgenic β-globin locus mice are shown. This graph is adapted from Noordermeer and de Laat 2008.

Figure 2

A schematic demonstrating the ontogeny of primitive and definitive erythroid cells from the earliest stem or progenitor cells that give rise to these lineages to more differentiated erythroid progenitors (ery. prog.) that then undergo maturation to give rise to mature erythrocytes (McGrath and Palis 2008, Sankaran, et al 2009). This scheme is shown in panel A. The various globin genes in mouse and humans that are expressed at each corresponding stage are shown below in panel B.