Poster abstracts
Poster number 19 submitted by Liuqing Yang
Cardiomyocyte-Specific Loss of eIF4G2 Disrupts Translational Homeostasis and Triggers Progressive Cardiac Remodeling and Late-onset Heart Failure
Liuqing Yang (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry), Eng-Soon Khor (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry), Alexander Chen (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry), Debojyoti Das (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry), Peng Yao (Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry)
Abstract:
Eukaryotic translation initiation factor, eIF4G2, is a homolog of eIF4G1 and has been shown to mediate noncanonical cap-independent or eIF4E-independent cap-dependent translation initiation. A recent clinical study suggested that the expression of eIF4G2 is correlated with the translation efficiency of 235 mRNAs in the hearts of 65 dilated cardiomyopathy patients and 15 non-failing controls, implying its critical role in heart failure. Our lab has shown that eIF4G2 promotes cardiac fibrosis by mediating the translation of profibrotic mRNAs. However, its role in cardiac disease and its molecular mechanism in modulating mRNA translation in cardiomyocytes (CMs) remains to be explored. To investigate the CM-specific effect of eIF4G2 loss-of-function, we generated a tamoxifen-inducible Myh6MCM-driven Eif4g2 fl/fl cKO mouse model. Eif4g2 cKO mice developed reduced left ventricular ejection fraction and late-onset mortality at 5-6 months after tamoxifen injection (post-TMX), while activation of the integrated stress response and fetal gene program was observed as early as 1 month post-TMX. RNA-seq and mass spectrometry results show decreased translation efficiency of genes enriched in cardiac muscle contraction and calcium signaling in cKO mouse hearts. Upregulated genes in cKO hearts were enriched in protein quality control pathways. These data suggest that eIF4G2 deficiency disrupts contractile protein expression while engaging compensatory proteostasis pathways, establishing an early molecular basis for the late-onset cardiac dysfunction. Ongoing studies are assessing intermediate (3 months) and late (~6 months) time points to determine how translational regulation and cardiac remodeling progress upon eIF4G2 depletion. We will combine whole-heart and cardiomyocyte-specific ribosome profiling (Ribo-seq and RiboTag-seq), RNA-seq, mass spectrometry, CLIP-seq, and 5'-UTR motif analyses to define global and selective translational programs regulated by eIF4G2 and the underlying biochemical mechanism in the heart. Together, these studies will establish how eIF4G2 governs cardiomyocyte translational control and how its loss drives pathological remodeling, thereby revealing novel therapeutic strategies to treat heart disease.
Keywords: eIF4G2, Translational control, Heart failure