Butyric Acid Modulates Developmental Globin Gene Switching in Man and Sheep

Abstract

The developmental switch from production of fetal (Υ) to adult (ß) globin occurs on a normally set biologic clock which proceeds even if the adult (ß) globin genes are defective. Preventing or reversing the globin gene switch would be beneficial for subjects with abnormal ß globin genes. We have now identified a class of agents which, when present in elevated plasma concentrations during gestation, appears to inhibit the Υ → ß globin gene switch in developing humans. Further investigation has shown that butyric acid and related compounds can increase Υ globin and decrease ß globin expression in erythroid cells cultured from subjects with diseases of abnormal ß globin. Butyrate compounds were therefore infused in an in vivo fetal animal model, and the globin switch was inhibited in most and reversed in some fetal lambs. These data suggest that inhibiting expression of abnormal ß globin genes may be possible in future generations. Histone modification may be a mechanism of action involved.

The developmental switch from production of γ globin to β globin results in significant morbidity when the β globin genes are defective. The globin switch has therefore been extensively studied, appearing to be set on a biologic clock and proceeding despite the site of blood production and solely on the basis of gestational age¹. We previously found that this developmental gene switch is delayed in human fetuses developing in the presence of maternal diabetes². A number of metabolites present in abnormal concentrations in these infants were therefore tested for effects on globin expression. One metabolite, a amino-n-butyric acid (ABA), was found to enhance γ globin and inhibit β globin expression in cultured neonatal erythroid cells³. Further investigation now shows that ABA, sodium butyrate and similar compounds can enhance γ,globin