Translocation of an erythroid-specific hypersensitive site in deletion-type hereditary persistence of fetal hemoglobin.
Hereditary persistence of fetal hemoglobin (HPFH) can involve large deletions which eliminate the 3' end of the beta-like globin gene cluster and more than 70 kilobases (kb) of flanking DNA. Blot hybridization revealed a DNase I-hypersensitive site extending from 1.1 to 1.4 kb downstream of the HPFH-1 3' deletion endpoint. The site was found in normal fetal and adult nucleated erythroid cells and in two erythroleukemia cell lines but not in nonerythroid cells and tissues. Simian virus 40 core enhancer-like sequences were found nonrandomly distributed within the boundaries of the site, which is contained in a fragment of known enhancer activity (E. A. Feingold and B. G. Forget, Blood, in press). A second hypersensitive site was found 0.5 kb upstream of the HPFH-1 3' deletion endpoint but was not erythroid specific. A third site, most prominent in fetal liver-derived erythroid cells, was found 1 kb upstream of the HPFH-2 deletion endpoint. As predicted by the locations of the deletion endpoints, the first two sites were translocated to within 12 kb of the A gamma gene in erythroid colonies derived from an HPFH-2 heterozygote and in hybrid mouse-human erythroid cells carrying the HPFH-2 deletion chromosome. Further analysis of this region showed that it was DNase I sensitive in erythroid and myeloid cells, indicating that it resides in an open chromatin domain. These observations suggest that alterations of chromatin structure flanking the fetal globin genes may contribute to abnormal gene regulation in deletion-type HPFH.
Department of Dermatology, University of Michigan, Ann Arbor 48109-0528.
J T
JT
Elder
W C
WC
Forrester
C
C
Thompson
D
D
Mager
P
P
Henthorn
M
M
Peretz
T
T
Papayannopoulou
M
M
Groudine
D000328:Adult; D001853:Bone Marrow / Q000378:metabolism; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002460:Cell Line; D002872:Chromosome Deletion; D004912:Erythrocytes / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000235:genetics*; D005333:Fetus; D006453:Hemoglobinopathies / Q000235:genetics*; D006801:Humans; D015183:Restriction Mapping; D013577:Syndrome; D014178:Translocation, Genetic
D005319:Fetal Hemoglobin