Cooperative Repression of γ-Globin by LYAR and NONO
- Author(s)
- Wu, D; Shangguan, W; Wang, X; Liu, T; Li, W; Liao, R; Meng, X; Xing, M; Zhu, Y; Zhang, R; Li, F; Chen, B; Huang, DCS; Zhao, Q;
- Journal Title
- Journal of Biological Chemistry
- Publication Type
- Oct 28
- Abstract
- Developmental silencing of γ-globin is a central event in hemoglobin switching, and reactivation of γ-globin expression effectively alleviates the severity of β-thalassemia and sickle cell disease (SCD). However, the precise regulatory mechanisms governing γ-globin repression remain incompletely defined. Here, we report that LYAR (Ly-1 antibody reactive clone, human homologue) and NONO (non-POU domain-containing octamer-binding protein) physically interact and co-occupy the γ-globin promoter to jointly repress its transcription. Knockdown of LYAR significantly reduced the recruitment of NONO to the γ-globin promoter. Notably, co-depletion of LYAR and NONO in K562 and HUDEP-2 cells resulted in additive induction of γ-globin expression that exceeded the effects of individual knockdowns and was comparable to BCL11A depletion, the established master regulator of HbF silencing. To validate these findings in vivo, we generated a conditional double knockout mouse model using IFN-inducible Mx1-Cre transgenic mice. Induced hematopoietic deletion of both LYAR and NONO in adult β-YAC transgenic mice led to significant reactivation of both murine embryonic globin genes and human γ-globin expression, indicating evolutionary conservation of this regulatory mechanism across mammals. Collectively, our findings identify LYAR and NONO as a functionally cooperative repressor complex in γ-globin silencing and establish co-targeting of these factors as a novel, and potent therapeutic strategy for elevating HbF levels in hemoglobinopathies.
- Publisher
- Elsevier
- Research Division(s)
- Blood Cells and Blood Cancer
- PubMed ID
- 42951140
- Publisher's Version
- https://doi.org/10.1016/j.jbc.2026.113702
- Open Access at Publisher's Site
https://doi.org/10.1016/j.jbc.2026.113702- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-11-03 08:45:09
Last Modified: 2026-11-03 08:45:22