| First Author | Li X | Year | 2021 |
| Journal | Nucleic Acids Res | Volume | 49 |
| Issue | 17 | Pages | 9711-9723 |
| PubMed ID | 34379783 | Mgi Jnum | J:331221 |
| Mgi Id | MGI:6764259 | Doi | 10.1093/nar/gkab671 |
| Citation | Li X, et al. (2021) Transcriptional silencing of fetal hemoglobin expression by NonO. Nucleic Acids Res 49(17):9711-9723 |
| abstractText | Human fetal globin (gamma-globin) genes are developmentally silenced after birth, and reactivation of gamma-globin expression in adulthood ameliorates symptoms of hemoglobin disorders, such as sickle cell disease (SCD) and beta-thalassemia. However, the mechanisms by which gamma-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 gamma-globin gene in human erythroid cells. We showed that NonO bound to the octamer binding motif, ATGCAAAT, of the gamma-globin proximal promoter, resulting in inhibition of gamma-globin transcription. Depletion of NonO resulted in significant activation of gamma-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 gamma-globin gene expression in adult beta-YAC mice, suggesting a conserved role for NonO during mammalian evolution. Thus, our data indicate that NonO acts as a novel transcriptional repressor of gamma-globin gene expression through direct promoter binding, and is essential for gamma-globin gene silencing. |
