Hemoglobin switching in humans is accompanied by changes in the ratio of the transcription factors, GATA-1 and SP1.
BACKGROUND
Understanding the mechanism of developmental regulation of hemoglobin switching has scientific as well as clinical relevance because of the influence of fetal hemoglobin (HbF) production in adulthood on the clinical manifestation of thalassemia and sickle cell anemia. We have previously found that the normal developmental patterns of globin gene expression are recapitulated in an experimental system of primary cultures that support differentiation of erythroid progenitors. We further found that high activities of the transcriptional activators, GATA-1 and SP1, are associated with normal adult erythroid differentiation.


METHODS
In the present work, we have studied, the activities of GATA-1 and SP1 during differentiation of cultured erythroid progenitors derived from cord blood and from fetal livers, as well as from beta zero-thalassemia patients.


RESULTS
The results showed high GATA-1 binding activity and very low SP1 activity in the fetal liver cultures. This pattern was in contrast to cultures derived from normal adult peripheral blood, in which both GATA-1 and SP1 activities were high. Cord blood cultures showed an additive combination of "adult" and "fetal" patterns. The progenitors derived from a beta zero-thalassemia patient with high HbF production showed "fetal" pattern. On the other hand, in cultures of 2 beta zero-thalassemia patients without high HbF, "adult" pattern was observed.


CONCLUSIONS
In the present work, we show that human fetal and adult erythroid progenitors are distinct in their transcription factors, and that the commitment to fetal or adult program occurs at a very early differentiation stage. Our studies also demonstrate that under anemic stress, recruitment of fetal progenitors may occur in adulthood.
Department of Hematology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
E R
ER
Bacon
N
N
Dalyot
D
D
Filon
L
L
Schreiber
E A
EA
Rachmilewitz
A
A
Oppenheim
D000328:Adult; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D004921:Erythropoietin / Q000494:pharmacology; D005312:Fetal Blood / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000096:biosynthesis* / Q000235:genetics; D050982:GATA1 Transcription Factor; D005812:Genes, Switch; D005914:Globins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008099:Liver / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014157:Transcription Factors / Q000097:blood / Q000378:metabolism*; D016335:Zinc Fingers; D017086:beta-Thalassemia / Q000097:blood
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D004921:Erythropoietin; D005914:Globins; D005319:Fetal Hemoglobin