α-Amino butyric acid cannot reactivate the silenced γ gene of the β locus YAC transgenic mouse

Butyric acid, a naturally occurring fatty acid, has been shown to increase fetal hemoglobin in BFUe cultures, in primates, and in patients with β chain hemoglobinopathies. The precise mechanism of γ gene induction by butyrate is unknown. Butyrate may induce fetal hemoglobin production in vivo by reactivation of silenced γ globin genes, by inhibiting the silencing of γ genes, or by both mechanisms. We examined the effects of butyrate on γ gene expression in transgenic mice carrying three types of constructs: μLCR(A)γ mice, which continue to express the γ gene in the adult stage of development at a level of one-third to one-fifth of the expression in the fetus; μLCR(A)γχβΔβ mice, which display correct developmental regulation of γ and β human globin genes and have low level γ globin expression in the adult; and β locus YAC mice, which display correct developmental regulation of ε, γ, and β globin genes and have a totally silenced γ gene in the adult stage. Animals were treated with a continuous infusion of α-amino butyric acid (α-ABA) for 7 days. In μLCR(A)γ mice α-ABA produced up to a 43-fold induction of γ and 9-fold induction of mouse α globin genes. In contrast, butyrate did not induce γ globin expression in the β locus YAC mice. However, the γ globin genes of β locus YAC mice were activated after administration of 5-azacytidine (5-azaC), and the level of γ globin expression was further increased by administration of α-ABA. These results suggest that butyrate cannot reactivate a totally silenced γ gene and that induction of fetal hemoglobin by this compound may require the presence of preactivated γ globin genes.