Transcriptional silencing of fetal hemoglobin expression by NonO. Issue 17 (11th August 2021)

• Record Type: Journal Article
• Authors: Li, Xinyu; Chen, Mengxia; Liu, Biru; Lu, Peifen; Lv, Xiang; Zhao, Xiang; Cui, Shuaiying; Xu, Peipei; Nakamura, Yukio; Kurita, Ryo; Chen, Bing; Huang, David C S; Liu, De-Pei; Liu, Ming; Zhao, Quan
• Is Part Of: Nucleic acids research. Volume 49:Issue 17(2021)
• Page Start: 9711
• Page End: 9723
• Publication Date: 2021-08-11
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkab671
• Languages: English
• ISSNs: 0305-1048

Abstract

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.