Poster abstracts
Poster number 66 submitted by Belal Chowdhury
Exploring the interplay between translational control and alternative splicing using multi-omics analyses of a neurohumoral-induced cardiac hypertrophy mouse model
Belal Chowdhury (1. Department of Biochemistry & Biophysics 2. Aab Cardiovascular Research Institute, University of Rochester School of Medicine & Dentistry), Debojyoti Das (Aab Cardiovascular Research Institute, University of Rochester School of Medicine & Dentistry), EngSoon Khor (Aab Cardiovascular Research Institute, University of Rochester School of Medicine & Dentistry), Feng Jiang (Aab Cardiovascular Research Institute, University of Rochester School of Medicine & Dentistry), Peng Yao (1. Department of Biochemistry & Biophysics 2. Aab Cardiovascular Research Institute, University of Rochester School of Medicine & Dentistry)
Abstract:
Alternative splicing (AS) generates mRNA isoforms with distinct coding potentials; however, the translational landscape of these isoforms remains underexplored, particularly regarding heart disease. Here, we explore how AS and translation interact to influence proteome reprogramming during cardiac remodeling. Using a multi-omics strategy combining RNA-seq, RiboTag-seq, Ribo-seq, and mass spectrometry, we profiled transcriptome- and translatome-wide AS isoforms in a β-adrenergic stimulation mouse model of heart disease. We identified a cohort of AS mRNAs with altered translational efficiency (TE), including key translation factors such as Rps6kb1, Eif4ebp1, and the RNA-binding protein Prrc2b. These findings suggest that AS events not only diversify transcript pools but also actively shape protein output in response to cardiac stress. We focused on Rps6kb1 (ribosomal protein S6 kinase beta-1), a key effector of the mTORC1 signaling pathway, which produces isoforms including full-length (FL) and a variant lacking exon 7 (ΔE7). Our data indicate that neurohormonal stimulation by isoproterenol (ISO) for 3 days induces a switch from the FL to the ΔE7 isoform to accommodate cardiac remodeling. This switch corresponds with increased ribosome association of the ΔE7 mRNA isoform, suggesting a shift in translational output during disease progression. Our findings indicate that AS of Rps6kb1 fine-tunes mTORC1 signaling and alters the translational efficiency of mTORC1-sensitive mRNAs with a 5' terminal oligopyrimidine sequence. This AS isoform switch may contribute to the increased kinase activity of RPS6KB1, thereby phosphorylating and activating downstream RPS6 to enhance translation. This stress-responsive AS switch may be required to trigger a rapid regulatory mechanism to adapt protein synthesis machinery under cardiac stress. Together, our data unveil RPS6KB1 as a key player linking AS to dynamic translational control during heart disease progression. This work establishes a foundational resource for understanding isoform-specific translation and presents new opportunities for therapeutic targeting of AS-translation circuits in cardiac disorders.
Keywords: Cardiac Hypertrophy, Alternative Splicing, Trnaslational Efficiency