Poster abstracts
Poster number 18 submitted by Sandip Chorghade
Dynamic expression of poly(A) binding protein N1 coordinates cardiac growth during development and disease
Joe Seimetz,Sandip Chorghade, Bo Zhang, Chaitali Misra (Department of Biochemistry , University of Illinois Urbana-Champaign), Stefan Bresson,Nicholas Conrad (Department of Microbiology, University of Texas Southwestern Medical Center), Xander Wehrens (Department of Molecular Physiology and Biophysics, Baylor College of Medicine), Auinash Kalsotra (Department of Biochemistry and Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign)
Abstract:
Global protein synthesis rates vary among tissues and cell types depending on their function and environment, and this variation is essential for normal development, growth, and homeostasis. Although the protein synthesis rate in the adult heart is one of the lowest among all tissues, it increases drastically in response to hypertrophic stimuli. Post-transcriptional changes can greatly affect translation of mRNAs. Particularly, the 3’UTR sequence and poly(A) tail length can influence translation through RNA binding proteins and non-coding RNAs. Nuclear poly(A) binding protein (PABPN1) is one such RBP that regulates mRNA translation via poly(A) tail length, mRNA transport, and alternative polyadenylation (ApA).
Here we report that cardiac PABPN1 protein levels are drastically downregulated during postnatal heart development. Strikingly, this down-regulation is post-transcriptional, cardiomyocyte-specific, evolutionarily conserved, and reversed with heart disease. Reduced PABPN1 protein levels in adult cardiomyocytes correlate strongly with the decrease in total protein synthesis, widespread changes in ApA, and low abundance of transcripts with longer poly(A) tails. Furthermore, we discovered that PABPN1-depleted cardiomyocytes are viable; but refractory to stimulus-induced hypertrophic growth due to their inability to activate new protein synthesis. Remarkably, forced expression of PABPN1 in the adult myocardium of transgenic mice stimulates pathological cardiac hypertrophy by modulating ApA, poly(A) tail length, and translation of mRNAs that are directly linked to maladaptive cardiac growth and heart failure. These data demonstrate that dynamic regulation PABPN1 facilitates transcriptome remodeling, protein synthesis, and subsequent growth of the mammalian heart in response to developmental and hypertrophic signals.
Keywords: PABPN1, Polyadenylation, Hypertrophy