Merck

Transcriptional silencing of fetal hemoglobin expression by NonO.

Nucleic acids research (2021-08-12)
Xinyu Li, Mengxia Chen, Biru Liu, Peifen Lu, Xiang Lv, Xiang Zhao, Shuaiying Cui, Peipei Xu, Yukio Nakamura, Ryo Kurita, Bing Chen, David C S Huang, De-Pei Liu, Ming Liu, Quan Zhao
ABSTRACT

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.

MATERIALS
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Product Description

Sigma-Aldrich
Anti-p54nrb/NonO Antibody, clone 78-1-C6, clone 78-1-C6, Upstate®, from mouse