MAZ regulates fetal hemoglobin repression by activating MYB transcription

Area of Science:

• Hematology
• Molecular Biology
• Genetics

Background:

• Beta-hemoglobinopathies, including sickle cell disease and beta-thalassemia, are prevalent genetic disorders with significant global health implications.
• Elevating fetal hemoglobin (HbF) is a key therapeutic strategy for managing these conditions.
• Understanding the regulation of gamma-globin (HBG) gene expression is crucial for developing effective treatments.

Purpose of the Study:

• To identify novel regulators of gamma-globin (HBG) expression in erythroid cells.
• To investigate the role of Myc-associated zinc finger (MAZ) in HBG gene regulation.
• To explore the potential of targeting the MAZ-MYB axis for therapeutic interventions in hemoglobinopathies.

Main Methods:

• Utilized HUDEP-2 cells and patient-derived beta-thalassemia cells.
• Performed MAZ depletion experiments using genetic manipulation techniques.
• Quantified HBG mRNA and protein levels via molecular assays.
• Assessed HbF percentages and HbF+ erythroid cell populations.
• Investigated MAZ binding at the MYB promoter and the effect of MYB restoration.

Main Results:

• MAZ acts as an indirect repressor of HBG expression in human erythroid cells.
• MAZ depletion significantly increased HBG mRNA and protein levels.
• Depletion of MAZ led to elevated HbF percentages and an increase in HbF+ erythroid cells.
• MAZ was found to bind to the promoter of MYB, a known HBG repressor.
• MAZ depletion reduced MYB expression, and MYB restoration reversed the HBG induction.

Conclusions:

• The study identified a novel MAZ-MYB regulatory axis controlling HBG expression.
• MAZ functions as an indirect repressor of gamma-globin, impacting HbF levels.
• MAZ represents a potential therapeutic target for increasing HbF in patients with beta-hemoglobinopathies.
• These findings offer a new strategy for managing sickle cell disease and beta-thalassemia.