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Transmembrane Protein ANTXR1 Regulates γ-Globin Expression by Targeting the Wnt/β-Catenin Signaling Pathway
Tingting Jin1,2, Zhaojun Zhang3, Yuanyuan Han1,2
1School of Medicine, Guizhou University, Guiyang, Guizhou 550025, China.
Journal of Immunology Research
|August 9, 2022
Summary
The membrane protein ANTXR1 regulates fetal hemoglobin (HbF) reactivation by activating the Wnt/β-catenin pathway and inhibiting SOX6. This discovery offers a new therapeutic target for beta-hemoglobinopathies.
Area of Science:
- Hematology
- Molecular Biology
- Genetics
Background:
- Fetal hemoglobin (HbF) reactivation is crucial for treating beta-hemoglobinopathies like sickle cell disease and thalassemia.
- The precise molecular mechanisms regulating HbF expression remain incompletely understood.
- Recent research suggests ANTXR1 influences gamma-globin levels, but its exact role is unclear.
Purpose of the Study:
- To elucidate the mechanism by which ANTXR1 regulates gamma-globin expression and fetal hemoglobin (HbF) reactivation.
- To investigate the role of the Wnt/β-catenin signaling pathway in ANTXR1-mediated HbF regulation.
- To identify downstream targets of ANTXR1 involved in controlling gamma-globin expression.
Main Methods:
- Overexpression and knockdown of ANTXR1 in K562, cord blood CD34+, and HUDEP-2 cells.
- Analysis of gamma-globin expression levels.
- Investigation of ANTXR1 interaction with LRP6 and its effect on Wnt/β-catenin signaling.
- Utilizing Wnt pathway modulators (XAV939, LiCl).
- Assessing the binding of c-Jun to the SOX6 gene promoter and SOX6 expression.
Main Results:
- ANTXR1 overexpression decreased and knockdown increased gamma-globin expression in tested cell lines.
- ANTXR1 promotes nuclear entry of β-catenin and activates Wnt/β-catenin signaling via LRP6.
- Modulation of ANTXR1 affected gamma-globin and Wnt/β-catenin signaling, reversible by XAV939 and LiCl.
- ANTXR1 overexpression enhanced c-Jun binding to the SOX6 promoter, increasing SOX6 transcription and protein levels.
- c-Jun acts as an initiator for SOX6 transcription, which silences gamma-globin.
Conclusions:
- ANTXR1 plays a critical role in regulating gamma-globin expression and HbF reactivation.
- The mechanism involves ANTXR1 activating the Wnt/β-catenin pathway and subsequently promoting c-Jun-mediated SOX6 transcription.
- This pathway represents a potential therapeutic target for beta-hemoglobinopathies.
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