Perrine S P, Faller D V, Swerdlow P, Miller B A, Bank A, Sytkowski A J, Reczek J, Rudolph A M, Kan Y W
Children's Hospital Oakland Research Institute, California 94609.
Ann N Y Acad Sci. 1990;612:134-40. doi: 10.1111/j.1749-6632.1990.tb24299.x.
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.
从胎儿型（γ）珠蛋白生成向成人型（β）珠蛋白生成的发育转换发生在一个正常设定的生物钟上，即使成人（β）珠蛋白基因的表达存在缺陷且产生很少或不产生蛋白质，就像在β地中海贫血中那样，这个生物钟仍会继续运行。阻止或逆转珠蛋白基因转换可能提供一种使异常珠蛋白基因“沉默”并维持胎儿珠蛋白基因表达的方法。我们已经鉴定出一类物质，当在孕期血浆浓度升高时，它们会抑制发育中的人类的γ→β珠蛋白基因转换。进一步研究表明，丁酸及相关化合物可以增加β地中海贫血患者培养的红系细胞中的γ珠蛋白表达并降低β珠蛋白表达。因此，将丁酸盐化合物注入一个体内胎儿动物模型中，在一些胎羊中珠蛋白转换受到抑制甚至逆转。维持活跃染色质结构的组蛋白高度乙酰化以及对γ珠蛋白启动子的影响似乎是其中涉及的作用机制。这些数据表明，未来通过药理学方法抑制异常β珠蛋白基因的表达可能用于治疗β珠蛋白疾病患者。
