Transcriptional silencing of fetal hemoglobin expression by NonO
- Author(s)
- 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;
- Journal Title
- Nucleic Acids Research
- Publication Type
- epub ahead of print
- 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.
- Research Division(s)
- Blood Cells And Blood Cancer
- PubMed ID
- 34379783
- Publisher's Version
- https://doi.org/10.1093/nar/gkab671
- Open Access at Publisher's Site
https://doi.org/10.1093/nar/gkab671- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2021-09-17 09:12:01
Last Modified: 2021-09-17 09:21:03