Transcriptional silencing of fetal hemoglobin expression by NonO.
Transcriptional silencing of fetal hemoglobin expression by NonO.
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NonO 对胎儿血红蛋白表达的转录沉默。
DOI：
10.1093/nar/gkab671
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发表时间：
2021-09-27
影响因子：
14.9
通讯作者：
Zhao Q
中科院分区：
文献类型：
--
作者：
Li X;Chen M;Liu B;Lu P;Lv X;Zhao X;Cui S;Xu P;Nakamura Y;Kurita R;Chen B;Huang DCS;Liu DP;Liu M;Zhao Q
人类胎儿珠蛋白（γ-珠蛋白）基因在出生后发育沉默，成年后γ-珠蛋白表达的重新激活可改善血红蛋白疾病的症状，例如镰状细胞病（SCD）和β-地中海贫血。然而，γ-珠蛋白表达精确调节的机制仍不完全清楚。在这里，我们发现NonO（不含POU结构域的八聚体结合蛋白）直接与SOX6相互作用，并抑制人红系细胞中γ-珠蛋白基因的表达。我们发现 NonO 与 γ-珠蛋白近端启动子的八聚体结合基序 ATGCAAAT 结合，从而抑制 γ-珠蛋白转录。 NonO 的消耗导致 K562、HUDEP-2 和原代人红系祖细胞中 γ-珠蛋白表达的显着激活。为了证实 NonO 在体内的作用，我们通过使用 IFN 诱导的 Mx1-Cre 转基因小鼠进一步产生了 NonO 的条件敲除。我们发现，诱导的 NonO 缺失重新激活了成年 β-YAC 小鼠的小鼠胚胎珠蛋白和人 γ-珠蛋白基因表达，这表明 NonO 在哺乳动物进化过程中具有保守的作用。因此，我们的数据表明，NonO 通过直接启动子结合充当 γ-珠蛋白基因表达的新型转录抑制因子，并且对于 γ-珠蛋白基因沉默至关重要。
Human fetal globin (γ-globin) genes are developmentally silenced after birth, and reactivation of γ-globin expression in adulthood ameliorates symptoms of hemoglobin disorders, such as sickle cell disease (SCD) and β-thalassemia. However, the mechanisms by which γ-globin expression is precisely regulated are still incompletely understood. Here, we found that NonO (non-POU domain-containing octamer-binding protein) interacted directly with SOX6, and repressed the expression of γ-globin gene in human erythroid cells. We showed that NonO bound to the octamer binding motif, ATGCAAAT, of the γ-globin proximal promoter, resulting in inhibition of γ-globin transcription. Depletion of NonO resulted in significant activation of γ-globin expression in K562, HUDEP-2, and primary human erythroid progenitor cells. To confirm the role of NonO in vivo, we further generated a conditional knockout of NonO by using IFN-inducible Mx1-Cre transgenic mice. We found that induced NonO deletion reactivated murine embryonic globin and human γ-globin gene expression in adult β-YAC mice, suggesting a conserved role for NonO during mammalian evolution. Thus, our data indicate that NonO acts as a novel transcriptional repressor of γ-globin gene expression through direct promoter binding, and is essential for γ-globin gene silencing.