Poster number 86 submitted by Sandip Chorghade
Post-transcriptional silencing of the nuclear poly(A) binding protein N1 is critical for postnatal maturation and function of the heart
Sandip Chorghade,Joe Seimetz,Bo Zhang,Chaitali Misra,Subhashish Natua (Department of Biochemistry,University of Illinois Urbana-Champaign.), Qinyu Hao,Kananganattu V. Prasanth (Department of Cell and Developmental Biology,University of Illinois Urbana-Champaign.), Xander Wehrens (Department of Molecular Physiology and Biophysics, Baylor College of Medicine), Jiwang Chen (Department of Medicine, University of Illinois Chicago), Auinash Kalsotra (Department of Biochemistry,Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign)
The nuclear poly(A) binding protein (PABPN1) is a ubiquitously expressed, evolutionarily conserved protein that controls many steps of the mRNA life cycle, including 3’-poly(A) tail elongation and alternative polyadenylation (ApA). Here we report that PABPN1 protein expression is post-transcriptionally silenced during postnatal heart development in humans, mice and rats; and this silencing is key for achieving adult, cardiac-specific gene expression profiles. Combining single-molecule RNA imaging and nucleo-cytoplasmic fractionations, we demonstrate that PABPN1 silencing during development occurs through a drastic shift in its mRNA localization: the mRNA is cytoplasmic in neonatal cardiomyocytes but becomes partially spliced, nuclear-retained, and translation-inaccessible in adult cardiomyocytes.
Importantly, cardiomyocyte-specific conditional loss- and gain-of-function studies revealed that premature elimination or 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 identify widespread changes in ApA and poly(A) tail lengths of cardiac transcripts during development, a significant portion of which are dependent on the postnatal silencing of PABPN1. Taken together, these results indicate that developmental silencing of PABPN1 through its regulated mRNA splicing and localization is critical for postnatal maturation and function of the heart
Keywords: PABPN1, Cardiac maturation, Cardiac Hypertrophy , Intron Retaintion