2 The regulation of human globin gene expression FRANK GROSVELD NIALL DILLON DOUGLAS HIGGS Blood cells originate from a self-renewing population of multipotential haemopoietic stem cells, originally derived from embryonic mesoderm, which generate progenitor cells that are irreversibly committed to one or other of the various haemopoietic lineages (Metcalf, 1989). The control of haemopoiesis is mediated by complex interactions between glycoproteins, termed haemopoietic growth factors, and membrane receptors of two families; the cytokine receptor family (e.g. erythropoietin receptor) and a tyrosine kinase receptor family (e.g. stem cell factor). When activated these receptors may modify gene expression and patterns of differentiation by a variety of, as yet ill-defined, cell signalling pathways (Metcalf, 1989; Olsson et al, 1992). Terminal differentiation along the erythroid pathway gives rise to mature red blood cells which almost exclusively synthesize haemoglobin due both to selective expression of the globin genes and differential stability of globin as opposed to non-globin mRNA. Following activation of the et and 13 loci toward the end of the third week of gestation, primitive-line erythroblasts derived from haemopoietic stem cells in the yolk sac produce embryonic haemoglobins (Gower-I ~2ea, Gower-II txze2, Portland-I ~2~t2 and Portland- II 42132). By 10 weeks post-conception, embryonic haemoglobins are no longer detectable and haemopoiesis involves definitive-line erythroblasts which are either derived from a second set of haemopoietic stem cells or from stem cells that have migrated from the yolk sac to the liver. These cells mainly produce fetal haemoglobin (HbF, et2"y2).In adults, the major site of erythropoiesis is the bone marrow in which definitive-line erythroblasts synthesize the major (HbA, 0~2132 ) and minor (HbA2, (X2~2) forms of adult haemoglobin (Weatherall and Clegg, 1981; Bunn and Forget, 1986; Stamatoyannopoulos et al, 1987). Over the past 30 years, a large number of naturally occurring mutations which down-regulate et (ec-thalassaemia) or [3 (13-thalassaemia) globin gene expression have been described (Higgs et al, 1989; Huisman, 1992; and Chapters 5 and 6 this volume). In addition many mutations which affect the transition from fetal (~/-globin) to adult ([3-globin) gene expression, referred to as hereditary persistence of fetal haemoglobin (HPFH) are known (see Bollekens and Forget, 1991 and Chapter 7 this volume). Baillidre's ClinicalHaematology--- 31 Vol. 6, No. 1, March1993 Copyright © 1993,byBailli~re TindaU ISBN0-7020-1692--6 Allrightsof reproduction in anyformreserved