Stopping the biologic clock for globin gene switching.
The developmental switch from production of fetal (gamma) to adult (beta) globin occurs on a normally set biologic clock which proceeds even if expression of the adult (beta) globin genes is defective and produces little or no protein, as in the beta-thalassemias. Preventing or reversing the globin gene switch could provide a way of keeping the abnormal globin genes "silent" and maintaining expression of the fetal globin gene. We have identified a class of agents which, when present in elevated plasma concentrations during gestation, inhibits the gamma----beta-globin gene switch in developing humans. Further investigation has shown that butyric acid and related compounds can increase gamma-globin and decrease beta-globin expression in cultured erythroid cells of patients with beta-thalassemia. Butyrate compounds were therefore infused in an in vivo fetal animal model, and the globin switch was inhibited and even reversed in some fetal lambs. Histone hyperacetylation, which maintains active chromatin structure, and an effect on the gamma-globin promoter appear to be mechanisms of action involved. These data suggest that inhibiting expression of abnormal beta-globin genes by pharmacologic means may in the future be possible for treatment of individuals with beta-globin disorders.
Perrine
S P
SP
Children's Hospital Oakland Research Institute, California 94609.
Faller
D V
DV
Swerdlow
P
P
Miller
B A
BA
Bank
A
A
Sytkowski
A J
AJ
Reczek
J
J
Rudolph
A M
AM
Kan
Y W
YW
D000755:Anemia, Sickle Cell / Q000097:blood*; D000818:Animals; D001683:Biological Clocks; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D002460:Cell Line; D002478:Cells, Cultured; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005319:Fetal Hemoglobin / Q000096:biosynthesis; D005333:Fetus; D015870:Gene Expression / Q000187:drug effects; D005914:Globins / Q000096:biosynthesis / Q000235:genetics*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D013006:Growth Hormone / Q000235:genetics; D006441:Hemoglobin A / Q000096:biosynthesis; D006801:Humans; D012756:Sheep; D013789:Thalassemia / Q000097:blood*; D014162:Transfection
D002087:Butyrates; D020148:Butyric Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013006:Growth Hormone; D005914:Globins; D006441:Hemoglobin A; D005319:Fetal Hemoglobin