Transcriptional mechanisms underlying hemoglobin synthesis

Abstract

The physiological switch in expression of the embryonic, fetal, and adult β-like globin genes has garnered enormous attention from investigators interested in transcriptional mechanisms and the molecular basis of hemoglobinopathies. These efforts have led to the discovery of cell type-specific transcription factors, unprecedented mechanisms of transcriptional coregulator function, genome biology principles, unique contributions of nuclear organization to transcription and cell function, and promising therapeutic targets. Given the vast literature accrued on this topic, this article will focus on the master regulator of erythroid cell development and function GATA-1, its associated proteins, and its frontline role in controlling hemoglobin synthesis. GATA-1 is a crucial regulator of genes encoding hemoglobin subunits and heme biosynthetic enzymes. GATA-1-dependent mechanisms constitute an essential regulatory core that nucleates additional mechanisms to achieve the physiological control of hemoglobin synthesis.

Figure 1.

The molecular basis of GATA-1 action. (A) Diagram of GATA-1 protein organization illustrating the amino and carboxyl fingers and posttranslational modification sites. The amino finger mediates FOG-1 binding, whereas the carboxyl finger mediates sequence-specific DNA binding to GATA motifs. M83 is an alternative translation start site of a leukemogenic form of GATA-1 in acute megakaryoblastic leukemia (Wechsler et al. 2002; Crispino 2005). V205 is mutated in dyserythropoietic anemia and thrombocytopenia (Nichols et al. 2000), and facilitates FOG-1 binding (Crispino et al. 1999). Phosphorylation (P) (Crossley and Orkin 1994; Towatari et al. 2004; Kadri et al. 2005; Yu et al. 2005; Zhao et al. 2006) and acetylation (Ac) (Hung et al. 1999; Lamonica et al. 2006, 2011) sites are depicted, as well as a sumoylated site (Collavin et al. 2004; Lee et al. 2009). (B) Multiple modes of GATA-1 function. GATA-1 activates or represses its target genes with or without FOG-1. The precise mode of transcriptional control is locus-specific, and representative target genes that conform to each regulatory mode are depicted (Bresnick et al. 2012). (C) GATA switch model. GATA switches are defined as a molecular transition in which one GATA factor replaces another from a chromatin site, which is often associated with an altered transcriptional output. In hematopoietic stem cells, select progenitors, and early-stage erythroblasts, GATA-2 occupies target loci. During erythropoiesis, poorly understood signals induce GATA-1 expression, and GATA-1 acquires the capacity to displace GATA-2 from chromatin, including sites at the Gata2 locus, which results in transcriptional repression. FOG-1 facilitates GATA-1 occupancy at select chromatin sites and GATA switches.

Figure 2.

(Top) Organization of the human and murine β-globin loci. The human locus contains β-globin genes expressed during embryogenesis (ε), fetal development (Gγ and Aγ), and the adult (δ and β). The mouse locus contains genes expressed during embryogenesis (εy and βH1) and adult (β major and β minor). The regions identified in Hispanic thalassemia and hereditary persistence of fetal hemoglobin (HPFH) mutations are described. The genomic structure of the human and murine β-globin and α-globin loci. Multiple DNaseI hypersensitive sites (HSs) are indicated by red bars. The human β-globin locus has five proximal HSs and additional HSs. The mouse locus has six proximal HSs and additional HSs. Among these HSs, HS1–4 are termed the locus control region (LCR). The LCR mediates high-level transcription of the β-globin-like genes. A large deletion of the LCR characterizes Hispanic thalassemia (Driscoll et al. 1989; Forrester et al. 1990). (Bottom) Organization of the human and murine α-globin loci. The human locus contains α-globin genes expressed during embryogenesis (ζ) and the adult (α1, α2, and θ). Similarly, the mouse locus contains α-globin genes expressed during embryogenesis (ζ) and the adult (α1 and α2). Analogous to the β-globin locus, there are several DNaseI HSs at the α-globin locus. A large deletion including these HSs and ζ has been identified in several patients (Hatton et al. 1990). Among these HSs, HS-40 (corresponding to HS-26 in the mouse locus) is considered to be functionally important.