YTHDF1 Regulates Pulmonary Hypertension through Translational Control of MAGED1

Area of Science:

• Molecular Biology
• Epigenetics
• Cardiovascular Research

Background:

• Posttranscriptional RNA modifications, including N6-methyladenosine (m6A), are increasingly recognized for their roles in cellular processes.
• Pulmonary hypertension (PH) involves complex vascular remodeling, but the contribution of m6A modification and its effectors remains largely unexplored.

Purpose of the Study:

• To investigate the role of m6A RNA modification and m6A effector proteins in the pathogenesis of pulmonary hypertension.
• To determine if m6A modification and YTHDF1 influence pulmonary artery smooth muscle cell (PASMC) behavior and PH development.

Main Methods:

• Quantification of m6A levels and YTHDF1 expression in human and experimental PH samples and cultured PASMCs.
• RNA immunoprecipitation sequencing to identify m6A-modified transcripts.
• Genetic manipulation (deletion/ablation) of YTHDF1 and MAGED1 in vivo and in vitro models of PH.
• Functional assays on PASMCs, including proliferation and phenotype analysis.

Main Results:

• Elevated m6A levels and YTHDF1 protein were observed in PH samples and hypoxic PASMCs.
• YTHDF1 deletion attenuated PASMC proliferation and PH development.
• MAGED1 was identified as an m6A-regulated gene; its ablation improved vascular remodeling and hemodynamics in PH models.
• YTHDF1-mediated MAGED1 translation was dependent on m6A modification and suppressed in METTL3-deficient cells.
• MAGED1 silencing inhibited hypoxia-induced PASMC proliferation by downregulating PCNA.

Conclusions:

• YTHDF1 promotes PASMC proliferation and PH pathogenesis by enhancing MAGED1 translation in an m6A-dependent manner.
• This study establishes m6A RNA modification as a critical mediator in pathological changes within PASMCs and the development of PH.
• Targeting the m6A-YTHDF1-MAGED1 axis presents a potential therapeutic strategy for pulmonary hypertension.