Nuclear Factors That Regulate Erythropoiesis

Abstract

INTRODUCTION Studies of erythroid transcription factors originate from efforts to identify and characterize the numerous tissue-specific and ubiquitous proteins that bind cis- regulatory motifs within the globin gene loci (Chapters 3 and 5). In addition to elucidating mechanisms of globin gene regulation and erythroid development, this approach has led to the discovery of nuclear proteins that function in a wide range of developmental processes. Experimental approaches and insights gained through studies of the globin loci have broad implications for understanding how transcription factors regulate the expression of individual genes and work together to coordinate cellular differentiation. Erythrocyte formation in the vertebrate embryo occurs in several distinct waves (see also Chapter 1). The first erythrocytes, termed primitive (EryP), arise in the extraembryonic yolk sac at mouse embryonic day 7.5 (E7.5) and weeks 3–4 in the human embryo. Later, erythropoiesis shifts to the fetal liver where adult-type (EryD, definitive) erythrocytes are produced. Finally, at birth, blood formation shifts to the bone marrow, and also the spleen in mice. EryPs and EryDs are distinguished by their unique cellular morphology, cytokine responsiveness, transcription factor requirements, and patterns of gene expression. Most notably, the expression of individual globin genes is developmentally regulated (Chapter 3). Understanding how transcription factors regulate the temporal control of β-like globin genes during mammalian development is of general interest to the study of gene regulation in higher eukaryotes and could eventually lead to new approaches to reactivate the human fetal γ-globin genes in patients with β chain hemoglobinopathies, such as sickle cell anemia and β thalassemia.