Stochastic expression of fetal hemoglobin in adult erythroid cells.

Abstract

The expression of fetal hemoglobin, Hb F, in the adult cells is cellularly restricted both in vivo and in culture. Because, in cultures of erythroid progenitors, subclones that express or fail to express Hb F are derived from the same erythroid stem cell, a mechanism must exist whereby Hb F expression segregates in the progeny of erythroid progenitors during their differentiation. We present mathematical analyses of experimental data which suggest that expression of Hb F in human adult erythroid cells occurs on a stochastic basis. We quantified Hb F expression among the subclones of erythroid bursts (clones) in vitro by labeling subclones with fluorescent anti-Hb F antibodies. The observed data were compared with predictions from a stochastic model with the assumption that the expression of Hb F in a subclone occurs with a probability P equal to the frequency of Hb F-expressing subclones in an experiment. There was good fit between the observed and predicted data with respect to: (i) the relative frequencies of monomorphic F+, monomorphic F-, and bimorphic F+/F- bursts, respectively; (ii) the size distributions among F+, F- and F+/F- bursts; and (iii) the proportions of subclones expressing Hb F within bimorphic F+/F- bursts. Given the hypothesis that erythroid progenitors which have an active Hb F program are less differentiated than cells which do not proceed to express Hb F, the stochastic event indicated by our analyses may be the probability that adult erythroid progenitor cells undergo terminal differentiation at an earlier stage than usual.

Developmental control via GATA factor interplay at chromatin domains

“…Stochastic transcriptional activity, in which a gene is actively transcribed in only certain cells in a population, has been observed in multiple systems (Stamatoyannopoulos et al, 1981;Ko, 1992;Walters et al, 1995;Graubert et al, 1998;Forsberg et al, 1999;Biggar and Crabtree, 2001), but has not been investigated in the context of GATA-1 and GATA-2 transcriptional regulation.…”

Direct evidence for interaction between human erythroid progenitor cells and a hemoglobin switching activity present in fetal sheep serum.

“…In support of this conclusion are the experiments with cfu(e) colonies. Although Hb F in the fetal sheep serum-grown cfu(e) was significantly lower than in fetal calf serum-grown cfu(e), Hb F synthesis in the former was still elevated, while in fetal sheep serum-grown bfu(e) colonies of the same bone marrow donors, Hb Previously, we presented evidence, based on immunofluorescence analyses of bursts, that the same bfu(e) can provide either F-producing or non-F-producing progeny (4,12,20). Other investigators, however, have suggested that in the adult person different bfu(e) produce Hb F-expressing or Hb F-non-expressing cells (21).…”

“…Their average size was 1,000-2,000 cells. Since the clones were transferred when they were composed of [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] calf serum-to-fetal calf serum controls (Fig. .3 the fetal sheep serum-grown part of a clone synthesizes less Hb F than the fetal calf serum-grown part.…”

βMinor-globin messenger RNA accumulation in reticulocytes governs improved erythropoiesis in β thalassemic mice after erythropoietin complementary DNA electrotransfer in muscles

“…48 The model states that increasing HbF synthesis during stress, thus possibly in response to intense Epo stimulation, involves the accelerated maturation of progenitors, leading to reprogramming or to recruiting erythroid progenitors that will give rise to F cells. 49 Investigating whether this model may account for anemia correction in ␤ thalassemic mice requires that erythropoiesis is maintained at a steady state, preferentially normocythemia. Indeed, exploration during acute Epo stimulation would not allow us to distinguish the effects observed in ␤ thalassemic mice from those previously described in normal animals.…”