The expression of the human β-like globin genes follows a well-orchestrated developmental pattern, undergoing two essential switches, the first one during the first weeks of gestation (ε to γ), and the second one during the perinatal period (γ to β). The γ- to β-globin gene switching mechanism includes suppression of fetal (γ-globin, HbF) and activation of adult (β-globin, HbA) globin gene transcription. In hereditary persistence of fetal hemoglobin (HPFH), the γ-globin suppression mechanism is impaired leaving these individuals with unusual elevated levels of fetal hemoglobin (HbF) in adulthood. Recently, the transcription factors KLF1 and BCL11A have been established as master regulators of the γ- to β-globin switch. Previously, a genomic variant in the KLF1 gene, identified by linkage analysis performed on twenty-seven members of a Maltese family, was found to be associated with HPFH. However, variation in the levels of HbF among family members, and those from other reported families carrying genetic variants in KLF1, suggests additional contributors to globin switching. ASF1B was downregulated in the family members with HPFH. Here, we investigate the role of ASF1B in γ- to β-globin switching and erythropoiesis in vivo. Mouse-human interspecies ASF1B protein identity is 91.6%. By means of knockdown functional assays in human primary erythroid cultures and analysis of the erythroid lineage in Asf1b knockout mice, we provide evidence that ASF1B is a novel contributor to steady-state erythroid differentiation, and while its loss affects the balance of globin expression, it has no major role in hemoglobin switching.

中文翻译：

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由于组蛋白伴侣 ASF1B 缺失导致轻度红细胞生成异常和 β 样珠蛋白基因表达失衡


人类 β 样珠蛋白基因的表达遵循精心策划的发育模式，经历两次重要的转换，第一次是在妊娠第一周期间（ε 到 γ），第二次是在围产期期间（γ 到 β） ）。 γ-至β-珠蛋白基因转换机制包括抑制胎儿（γ-珠蛋白，HbF）和激活成人（β-珠蛋白，HbA）珠蛋白基因转录。在胎儿血红蛋白 (HPFH) 遗传性持续存在中，γ-珠蛋白抑制机制受损，导致这些个体在成年后胎儿血红蛋白 (HbF) 水平异常升高。最近，转录因子 KLF1 和 BCL11A 已被确定为 γ- 至 β- 珠蛋白开关的主要调节因子。此前，通过对马耳他家族 27 名成员进行连锁分析鉴定出 KLF1 基因的基因组变异与 HPFH 相关。然而，家庭成员之间以及其他报道的携带 KLF1 遗传变异的家庭成员之间 HbF 水平的差异表明，珠蛋白转换还有其他因素。 ASF1B 在 HPFH 家族成员中表达下调。在这里，我们研究了 ASF1B 在体内 γ- 至 β-珠蛋白转换和红细胞生成中的作用。小鼠-人种间 ASF1B 蛋白同一性为 91.6%。通过对人类原代红系培养物中的敲低功能测定以及对 Asf1b 敲除小鼠中的红系谱系分析，我们提供了证据，证明 ASF1B 是稳态红系分化的新贡献者，虽然它的缺失影响了珠蛋白表达的平衡，但在血红蛋白转换中没有主要作用。