YTHDF3 modulates hematopoietic stem cells by recognizing RNA m6A modification on Ccnd1
Xiaofei Zhang1, Tingting Cong1, Lei Wei2
1School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084.
Haematologica
|February 3, 2022
Summary
N6-methyladenosine (m6A) RNA modification is crucial for hematopoietic stem cells (HSC). This study identifies Cyclin D1 (Ccnd1) as a key target, regulated by METTL3 and YTHDF3, to maintain HSC function.
Area of Science:
- Hematology
- Epigenetics
- Molecular Biology
Background:
- Hematopoietic stem cells (HSC) are vital for lifelong blood cell production.
- N6-methyladenosine (m6A) is a prevalent RNA modification regulating gene expression.
- m6A "writer" genes like METTL3 are essential for HSC function, but the role of m6A "readers" is unclear.
Purpose of the Study:
- To identify the m6A "reader" protein that modulates HSC function.
- To elucidate the mechanism by which m6A regulates HSC reconstitution capacity.
Main Methods:
- Investigated the roles of Ythdf3 and Ccnd1 in HSC function.
- Analyzed the impact of Ythdf3 and Mettl3 dysfunction on Ccnd1 translation.
- Examined the m6A modification on Ccnd1's 5' untranslated region.
Main Results:
- Ythdf3 and Ccnd1 dysfunction severely impaired HSC reconstitution, mimicking Mettl3 deficiency.
- Ythdf3 and Mettl3 deficiency led to Ccnd1 translational defects.
- METTL3 and YTHDF3 regulate HSCs by impacting m6A modification on Ccnd1 mRNA.
- Restoring Ccnd1 expression rescued Ythdf3-deficient HSCs and partially rescued Mettl3-compromised HSCs.
Conclusions:
- Identified Ccnd1 as a direct target of METTL3 and YTHDF3 in HSC regulation.
- Demonstrated that YTHDF3 deciphers m6A signals on Ccnd1 to control HSC reconstitution.
- Established a novel m6A-mediated pathway involving Ccnd1 for HSC maintenance.
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