mRNA translational specialization by RBPMS presets the competence for cardiac commitment in hESCs

Area of Science:

• Developmental Biology
• Molecular Biology
• Stem Cell Biology

Background:

• Organ development blueprints are established early in embryogenesis.
• Transcriptional and epigenetic mechanisms are traditionally thought to preset developmental trajectories.
• The role of post-transcriptional regulation, specifically mRNA translation, in fate determination remains less understood.

Purpose of the Study:

• To investigate the role of mRNA translation in pre-setting cardiac fate competence in human embryonic stem cells (hESCs).
• To identify specific molecular mechanisms controlling translation during early cardiac development.
• To elucidate the function of RNA-binding protein motif sequence-s (RBPMS) in cardiac lineage specification.

Main Methods:

• Utilized human embryonic stem cells (hESCs) and cardiac organoid models.
• Investigated the recruitment of RBPMS to ribosomes in hESCs.
• Analyzed the impact of RBPMS loss on mRNA translation, focusing on translation initiation factors (e.g., EIF3 complex, EIF5A) and target mRNAs (e.g., WNT signaling components).
• Assessed cardiac mesoderm specification and organoid development following RBPMS manipulation.

Main Results:

• RBPMS is recruited to active ribosomes in hESCs, controlling the translation of key cardiac commitment factors, including Wingless/Integrated (WNT) signaling components.
• Loss of RBPMS specifically and severely impairs cardiac mesoderm specification, leading to defects in human cardiac organoid patterning and morphogenesis.
• Mechanistically, RBPMS specializes mRNA translation through 3'UTR binding and promotion of translation initiation, with RBPMS loss causing defects in ribosome recruitment due to EIF3 complex retention and EIF5A depletion.

Conclusions:

• Cardiac fate competence is preset in pluripotency by a specialized mRNA translation circuit governed by RBPMS.
• RBPMS plays a critical role in regulating translation initiation and ribosome recruitment, essential for cardiac lineage specification.
• This study highlights specialized mRNA translation as a key programming mechanism for future cell fate trajectories during embryogenesis.