Perrine S P, Swerdlow P, Faller D V, Qin G, Rudolph A M, Reczek J, Kan Y W
Children's Hospital Oakland Research Institute, CA.
Adv Exp Med Biol. 1989;271:177-83. doi: 10.1007/978-1-4613-0623-8_18.
The developmental switch from production of fetal (gamma) to adult (beta) globin occurs on a normally set biologic clock which proceeds even if the adult (beta) globin genes are defective. Preventing or reversing the globin gene switch would be beneficial for subjects with abnormal beta globin genes. We have now identified a class of agents which, when present in elevated plasma concentrations during gestation, appears to inhibit 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 erythroid cells cultured from subjects with diseases of abnormal beta 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 beta globin genes may be possible in future generations. Histone modification may be a mechanism of action involved. The developmental switch from production of gamma globin to beta globin results in significant morbidity when the beta 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 age. We previously found that this developmental gene switch is delayed in human fetuses developing in the presence of maternal diabetes. A number of metabolites present in abnormal concentrations in these infants were therefore tested for effects on globin expression.(ABSTRACT TRUNCATED AT 250 WORDS)
从胎儿（γ）珠蛋白生成向成人（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）珠蛋白基因存在缺陷，这个生物钟仍会继续运行。对于β珠蛋白基因异常的个体，阻止或逆转珠蛋白基因转换将是有益的。我们现已鉴定出一类物质，在孕期血浆浓度升高时，这类物质似乎能抑制发育中的人类γ向β珠蛋白基因的转换。进一步研究表明，丁酸及相关化合物可增加患有β珠蛋白异常疾病个体所培养的红系细胞中γ珠蛋白的表达并降低β珠蛋白的表达。因此，将丁酸盐化合物注入一个体内胎儿动物模型中，大多数胎儿羔羊的珠蛋白转换受到抑制，部分胎儿羔羊的珠蛋白转换则发生逆转。这些数据表明，未来有可能抑制异常β珠蛋白基因的表达。组蛋白修饰可能是其中涉及的一种作用机制。当β珠蛋白基因存在缺陷时，从γ珠蛋白生成向β珠蛋白生成的发育转换会导致严重发病。因此，人们对珠蛋白转换进行了广泛研究，它似乎由生物钟设定，且无论造血部位如何，仅根据胎龄进行。我们之前发现，在患有母体糖尿病的情况下发育的人类胎儿中，这种发育基因转换会延迟。因此，对这些婴儿体内浓度异常的多种代谢物进行了珠蛋白表达影响测试。（摘要截选至250词）
