| RRC ID |
90115
|
| Author |
Dong Z, Ye Y, Zhang W, Luo H, Li J, Zhang Q, Zhang X, Guo X, Xu X.
|
| Title |
MYB represses ζ-globin expression through upregulating ETO2.
|
| Journal |
Acta Biochim Biophys Sin (Shanghai)
|
| Abstract |
Reactivating the embryonic ζ-globin gene represents a potential therapeutic approach to ameliorate the severe clinical phenotype of α-thalassemia and sickle cell disease. The transcription factor MYB has been extensively proven to be a master regulator of the γ-globin gene, but its role in the regulation of ζ-globin remains incompletely understood. Here, we report a mechanistic study on the derepression of ζ-globin both in vivo and in vitro. We show that MYB depletion in mouse models and human hematopoietic stem cells leads to consistent and remarkable reactivation of ζ-globin. Furthermore, multiomics analysis and functional validation of MYB-knockout and wild-type cell lines reveal that ETO2 functions as a novel repressor of ζ-globin through coordination with NuRD nucleosome remodeling and the deacetylation complex to modulate histone deacetylation of ζ-globin. Additionally, we evaluate the clinical significance of these findings by knocking out ETO2 in primary CD34 + cells from nondeletional hemoglobin H patients, which results in a significant increase in ζ-globin expression. The RNA-seq data reveal that key erythroid genes are more co-regulated by Myb and Eto2 than by Myb and Klf1, highlighting a distinctly enhanced erythroid-specific transcriptional impact within the MYB-ETO2 regulatory axis. Compared with ETO2 knockout alone, codepletion of ETO2 and BCL11A did not significantly activate ζ-globin, suggesting that the MYB-ETO2 pathway primarily silences ζ-globin. Our study reveals a linear MYB-ETO2 signaling pathway crucial for ζ-globin repression and offers new targets for treating α-thalassemia and sickle cell disease.
|
| Volume |
57(9)
|
| Pages |
1457-1468
|
| Published |
2025-1-2
|
| DOI |
10.3724/abbs.2024239
|
| PMID |
39757769
|
| PMC |
PMC12536454
|
| MeSH |
Animals
Hematopoietic Stem Cells / metabolism
Humans
Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism
Mice
Mice, Knockout
Proto-Oncogene Proteins c-myb* / genetics
Proto-Oncogene Proteins c-myb* / metabolism
Up-Regulation*
|
| Resource |
| Human and Animal Cells |
HUDEP-2(RCB4557) |
