Talk abstracts
Talk on Friday 02:30-02:45pm submitted by Aleksandr Ivanov
Loss of function of RNA-binding protein PRRC2B causes translation dysregulation and congenital heart defects
Aleksandr Ivanov, Debojyoti Das, EngSoon Khor, Feng Jiang (Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester), Jiali He, Yui Kawakami (Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester), Peng Yao (Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester, corresponding author)
Abstract:
Pro-rich Coiled-coil 2B (PRRC2B), regulates the translation initiation of a selective cohort of mRNAs required for cell proliferation [1]. We identified two alternative spliced isoforms of PRRC2B mRNA across various human and mouse organs. CRISPR-Cas9 knock-in of a congenital heart disease-associated human nonsense mutation in the exon 16 of the Prrc2b gene causes the depletion of the full-length Prrc2b mRNA but not the alternatively spliced exon 16-excluded form ∆E16, leading to mild cardiac hypertrophy at an early stage. Global knockout of the Prrc2b gene (null; both isoforms are absent) caused patent ductus arteriosus and neonatal lethality in mice. Transcriptome profiling analyses of embryonic mouse hearts demonstrated a significant overall downregulation of smooth muscle-specific genes in mice. Polysome-seq in PRRC2B knockout and knockdown human cells and global Prrc2b-null mouse hearts identified a cohort of translationally inhibited mRNAs that encode essential factors required for cardiovascular development. Our IP-MS study showed PRRC2B isoforms share an interactome, including the eIF4G2-containing translation initiation complex. Intriguingly, only full-length PRRC2B was associated with nuclear proteins, consistent with its dual localization in both the nucleus and the cytoplasm, while ∆E16 is predominantly localized in the cytoplasm. Mutagenesis mapping revealed additional RNA-binding domains beyond the exon 16-encoded RG repeats containing domain in PRRC2B. In summary, our phenotypic characterization of Prrc2b genetic knockout mouse models uncovered a redundant function of the two alternative splicing isoforms of PRRC2B in maintaining normal cardiovascular development and function. This study will shed light on the significance of PRRC2B in cardiovascular disease diagnosis and treatment. Future research on different mRNA targets and protein partners for full-length and ∆E16 PRRC2B will determine the function of each isoform.
References:
1. 1. Jiang, Feng et al. “RNA binding protein PRRC2B mediates translation of specific mRNAs and regulates cell cycle progression.” Nucleic acids research vol. 51,11 (2023): 5831-5846. doi:10.1093/nar/gkad322
Keywords: PRRC2B, translation, cardiovascular