Abstract 4143064: Dynamic expression poly(A) binding protein N1 coordinate cardiac growth during development and disease.

The nuclear poly(A) binding protein (PABPN1) is a ubiquitously expressed, evolutionarily conserved protein that actively involved in 3’-poly(A) tail elongation and alternative polyadenylation (ApA). Here we report that PABPN1 protein expression is post-transcriptionally silenced during postnatal heart development especially in cardiomyocytes but re-expressed during heart failure. Combining single-molecule RNA imaging and nucleo-cytoplasmic fractionations, we demonstrate that PABPN1 silencing in healthy cardiomyocytes occurs through a drastic shift in its mRNA localization: the mRNA is cytoplasmic in neonatal cardiomyocytes but remain incompletely spliced, nuclear speckle-detained, and thus translation-inaccessible in adult cardiomyocytes. Surprisingly during cardiac disease, the stored Pabpn1 mRNA undergoes splicing and transported to cytoplasm for translation. Importantly, cardiomyocyte-specific conditional loss- and gain-of-function studies revealed that persistent expression of PABPN1 in the mouse myocardium provokes major structural and functional abnormalities, resulting in heart failure and death. Using nanopore-based direct RNA and high-resolution illumina sequencing, we identified widespread changes in ApA and poly(A) tail lengths of cardiac transcripts during disease contributing significantly to their expression. Taken together, these results indicate that developmental silencing of PABPN1 through its regulated mRNA splicing and localization is critical for function of the heart while its persistence expression is essential for cardiomyopathy progression.