Understanding α‐Globin Gene Regulation: Aiming to Improve the Management of Thalassemia

Abstract

Over the past 50 years, many advances in our understanding of the general principles controlling gene expression during hematopoiesis have come from studying the synthesis of hemoglobin. Discovering how the alpha- and beta-globin genes are normally regulated and documenting the effects of inherited mutations that cause thalassemia have played a major role in establishing our current understanding of how genes are switched on or off in hematopoietic cells. Previously, nearly all mutations causing thalassemia have been found in or around the globin loci, but rare inherited and acquired trans-acting mutations are being found more often. Such mutations have demonstrated new mechanisms underlying human genetic disease. Furthermore, they are revealing new pathways in the regulation of globin gene expression that, in turn, may open up new avenues for improving the management of patients with common types of thalassemia.

ATRX-mediated chromatin association of histone variant macroH2A1 regulates α-globin expression

“…Deregulation of members of the SWI/SNF family is implicated in various cancers and mental retardation (MR) syndromes, including ATRX (a-thalassemia/MR, X-linked), (Wilson and Roberts 2011). Mutations in ATRX, predominantly found in the H3K9me3-binding ADD (ATRX-DNMT3-DNMT3L) and/or helicase domains, are associated with ATRX syndrome (Higgs et al 2005;Iwase et al 2011). This syndrome is characterized by MR and a-thalassemia-a loss of a-globin gene production (Higgs et al 2005).…”

“…This syndrome is characterized by MR and a-thalassemia-a loss of a-globin gene production (Higgs et al 2005). However, the mechanisms by which HBA (hemoglobin a) gene repression occurs are unknown (Higgs et al 2005).In addition to its role in regulating gene expression, ATRX acts in concert with Daxx to deposit the H3 variant H3.3 specifically at telomeres (Drane et al 2010;Goldberg et al 2010;Lewis et al 2010), and ATRX deficiency results in loss of telomere integrity Wong et al 2010;Heaphy et al 2011). However, it remains unclear how loss of functional ATRX protein affects the global chromatin landscape of ATRX patients, which may have tissue-specific effects (Berube 2011).…”

Controlling -globin: a review of -globin expression and its impact on -thalassemia

“…17,19 Analysis of the other elements in transgenic mice indicate that combinations of HS-10, HS-33 and HS-48 in small constructs are able to direct tissue and developmental stage specific expression but are unable to drive substantial levels of α-globin expression. 20 This has been further confirmed in a newly identified mutation in the enhancer which resulted in an α-thalassemia phenotype. 19 The mutation involved the deletion of a 16 kb region including the HS-40 and HS-48 while leaving HS-33 and HS-10 intact.…”

Developmental expression of human hemoglobins mediated by maturation of their subunit interfaces

“…However, we found that if the concentrations are reduced to the nanomolar range, which is below their tetramer dissociation constants, the elution patterns are radically different from one another ( Fig. 2) indicative of significant variability in their subunit interface strengths as shown by the red lines that have been added to the scheme of Higgs et al 3 shown in Figure 1.…”

“…1) represents a major model of developmental biology, which is currently explained by the ''switching'' on and off of the various globin genes, known as ontogeny. 4 The process is initiated by various transcription factors that interact with upstream regulatory regions of the two globin gene clusters 3 ( Fig. 1).…”