What are the molecular switches for the various globin genes (embryonal, foetal and adult) and what triggers them?

Abstract

Human haemoglobins are tetramers of two a globins, i.e. x or a, and two non-a globins, i.e. e, Gg, Ag, d, or b, each associated with a haem group. The seven normal haemoglobins that appear at different stages and are developmentally controlled, are embryonic; Hb Gower 1 (x2e2), Hb Portland (x2g2), and HbGower 2 (a2e2), the foetal HbF (a2 Gg2) and (a2 Ag2) and the adult, HbA2 (a2d2) and HbA (a2b2). Genes at chromosome 11p15.4 that encode the globins of the b cluster, are arranged 5’ to 3’ in their order of expression during development. The molecular mechanisms that determine the expression of these genes have been the subject of much investigation, have revealed some of the basic components and will be summarized here. Studies of patients who carry the so-called Dutch and Hispanic b thalassaemia mutations indicated that key regulatory elements, situated around 6 – 20 kb upstream of the e gene, are required for high-level globin gene expression (1). They comprise two DNase-1-hypersensitive sites (DNase-1 HS) which are specific to erythroid cells and located 17 kb upstream of the e gene and 18 kb downstream of the human b globin gene, respectively (2, 3). In contrast to other DNase-1 HS near individual globin genes, they are present at all developmental stages. The 5’ sites, comprise the Locus Control Region (LCR) termed (5’) HS1, HS2, HS3 and HS4 while 3’HS1 (4) is 3’ to the b gene. A 5’HS5 sequence, upstream of the HS1 to HS4, is constitutive.