MYB represses ζ-globin expression through upregulating ETO2

Area of Science:

• Hematology
• Molecular Biology
• Gene Regulation

Background:

• Reactivating embryonic ζ-globin (ζ-globin) is a promising therapeutic strategy for severe hemoglobinopathies like α-thalassemia and sickle cell disease.
• The transcription factor MYB is a known regulator of γ-globin, but its precise role in ζ-globin regulation is not fully understood.

Purpose of the Study:

• To elucidate the regulatory mechanism of ζ-globin expression.
• To identify novel therapeutic targets for α-thalassemia and sickle cell disease by investigating the role of MYB and its interacting partners in ζ-globin regulation.

Main Methods:

• In vivo and in vitro studies using mouse models and human hematopoietic stem cells.
• MYB depletion experiments.
• Multiomics analysis (including RNA-seq) and functional validation of MYB-knockout and wild-type cell lines.
• ETO2 knockout in primary CD34+ cells from patients with nondeletional hemoglobin H.

Main Results:

• MYB depletion consistently reactivated ζ-globin expression in both mouse models and human cells.
• ETO2 was identified as a novel repressor of ζ-globin, acting via the NuRD complex to modulate histone deacetylation.
• ETO2 knockout in patient-derived cells significantly increased ζ-globin expression.
• The MYB-ETO2 axis showed a stronger erythroid-specific transcriptional impact than MYB-Klf1 interactions.
• The MYB-ETO2 pathway appears to be the primary mechanism for ζ-globin silencing.

Conclusions:

• A linear signaling pathway involving MYB and ETO2 is crucial for repressing ζ-globin.
• This pathway represents a novel therapeutic target for treating α-thalassemia and sickle cell disease.